Antipsychotics for acute and chronic pain in adults

  • Comment
  • Review
  • Intervention

Authors


Abstract

Background

This is an updated version of the original Cochrane review published in Issue 4, 2008. The role of antipsychotics as adjuvant analgesics is a subject of longstanding controversy. Neuroleptanalgesia (that is a state of quiescence, altered awareness, and analgesia produced by a combination of taking an opioid analgesic and an antipsychotic), an established term for the management of acute pain, was shown to negatively influence disease course and total mortality in unstable angina patients. Nevertheless, antipsychotics are used to treat chronic pain (for example chronic headache, fibromyalgia and diabetic neuropathia). With atypical antipsychotics, a new class of antipsychotics, both fewer extrapyramidal side effects and additional benefits may be available.

Objectives

To assess the analgesic efficacy and adverse effects of antipsychotics in acute or chronic pain in adults.

Search methods

The following databases were searched: CENTRAL, on The Cochrane Library, (Issue 12 of 12, 2012); MEDLINE (1966 to 11/1/2013); EMBASE (1980 to 2013 week 03) and PsycINFO 1806 to Jan week 3 2013. Searches were run originally in 2007 and then again in 2011 and 2013.

Selection criteria

Randomised controlled trials (RCTs) of adults prescribed any dose of an oral antipsychotic for acute or chronic pain, where subjective pain assessment was described as either the primary or a secondary outcome, were included in this review.

Data collection and analysis

Data were extracted by two independent review authors, and results were compared for differences. Discrepancies were resolved by discussion. All trials were quality scored according to the methods set out in section six of the Cochrane Handbook for Systematic Reviews of Interventions.

Main results

A total of 770 participants were involved in the 11 included studies. Data from five included randomised double-blind studies showed beneficial effects of antipsychotics in the treatment of acute and chronic pain. Quantitative analysis of these studies showed a significant reduction of mean pain intensity after administration of the antipsychotic compared to placebo or another active compound, weighted mean difference (WMD) -1.78 (95% CI -2.71 to -0.85) for the continuous data; and relative risk (RR) 0.43 (95% CI 0.25 to 0.73), number needed to treat to benefit (NNT) 2.6 for the dichotomous data. Nevertheless, the test for heterogeneity was significant for both the continuous data (P = 0.0007) and the dichotomous data (P = 0.04). Obviously this makes the calculated NNT less reliable and caution is warranted when interpreting these results.

The most frequently reported adverse effects were extrapyramidal (that is involuntary movements, parkinsonism and akathisia) and sedating effects.

Authors' conclusions

The recent search found five new studies which were all excluded, so the review remains the same as previously.

Antipsychotics might be used as an add-on therapy in the treatment of painful conditions. Nevertheless, extrapyramidal and sedating side effects have to be considered before using antipsychotics for treating painful conditions.

Results for antipsychotics in the treatment of different painful conditions are mixed and most sample sizes in the reviewed RCTs are small. Further studies on atypical antipsychotics in larger double-blind placebo-controlled studies that include standardised pain assessment and documentation are warranted.

Résumé scientifique

Les antipsychotiques pour traiter la douleur aiguë et chronique chez l'adulte

Contexte

Ceci est une version mise à jour de la revue Cochrane originale publiée dans le numéro 4, 2008. Le rôle des antipsychotiques en tant qu'analgésiques adjuvants fait l'objet d'une longue controverse. Il a été démontré que la neuroleptanalgésie (qui est un état de quiescence, d'altération de la conscience et d'analgésie produite par la prise d'un analgésique opioïde combiné avec un antipsychotique), une forme établie pour la prise en charge de la douleur aiguë, influence négativement le cours de la maladie et la mortalité totale chez des patients atteints d'angor instable. Néanmoins, les antipsychotiques sont utilisés pour traiter la douleur chronique (par exemple la céphalée chronique, la fibromyalgie et la neuropathie diabétique). Avec des antipsychotiques atypiques, une nouvelle classe de neuroleptiques, ayant à la fois moins d'effets secondaires extrapyramidaux et davantage de bénéfices, pourrait être disponible.

Objectifs

Évaluer l'efficacité analgésique et les effets indésirables des neuroleptiques contre la douleur aiguë ou chronique chez l'adulte.

Stratégie de recherche documentaire

Les bases de données suivantes ont été consultées : CENTRAL, sur La Bibliothèque Cochrane, (numéro 12 sur 12, 2012) ; MEDLINE (de 1966 à 11/1/2013) ; EMBASE (de 1980 à 2013 semaine 3) et PsycINFO de 1806 à la 3ème semaine de janvier 2013. Des Recherches ont été effectuées pour la première fois en 2007 et encore en 2011 et 2013.

Critères de sélection

Les essais contrôlés randomisés (ECR) portant sur des adultes ayant été prescrits une dose quelconque d'antipsychotique orale pour la douleur aiguë ou chronique, où l'évaluation subjective de la douleur a été décrite comme critère de jugement primaire ou secondaire, ont été inclus dans cette revue.

Recueil et analyse des données

Les données ont été extraites par deux auteurs indépendants de la revue et les résultats ont été comparés pour évaluer les différences. Les divergences ont été résolues par discussion. Tous les essais ont été notés en fonction de leur qualité selon les méthodes décrites dans la section six des du Manuel Cochrane sur les Revues Systématiques des Interventions.

Résultats principaux

Un total de 770 participants a été impliqué dans 11 études incluses. Les données issues de cinq études, incluant des essais randomisés en double aveugle, ont montré les effets bénéfiques des neuroleptiques pour le traitement de la douleur aiguë et chronique. L'analyse quantitative de ces études a montré une réduction significative de l'intensité de la douleur moyenne après l'administration de l'antipsychotique par rapport à un placebo ou à un autre composé actif, la différence moyenne pondérée (DMP) à 95 % -1,78 (IC à 95 % de -2,71 à -0,85) pour les données continues ; et le risque relatif (RR) de 0,43 (IC à 95 % 0,25 à 0,73), le nombre de sujets à traiter pour observer un bénéfice (NST) de 2,6 pour les données dichotomiques. Néanmoins, le test d'hétérogénéité était significatif à la fois pour les données continues (P =0,0007) et les données dichotomiques (P =0,04). Bien évidemment, cela rend les calculs NST moins fiables et il est nécessaire d'être prudent lors de l'interprétation de ces résultats.

Les effets indésirables les plus fréquemment rapportés étaient des effets extrapyramidaux (qui sont des mouvements involontaires, la maladie de Parkinson et l'acathésie) et des effets sédatifs.

Conclusions des auteurs

Les récentes recherches ont découvert cinq nouvelles études qui ont toutes été exclues, la revue reste donc la même que précédemment.

Les neuroleptiques peuvent être utilisés comme traitement d'appoint dans le traitement des états douloureux. Néanmoins, les effets secondaires extrapyramidaux et sédatifs doivent être pris en compte avant d'utiliser des neuroleptiques pour traiter les états douloureux.

Les résultats pour les neuroleptiques dans le traitement de différentes conditions douloureuses sont contrastés et la plupart des tailles d'échantillons dans les ECR de la revue sont réduites. D'autres études sur les antipsychotiques atypiques, avec des études plus nombreuses en double aveugle contrôlées par placebo, qui incluent une évaluation de la douleur standardisée et la documentation, sont nécessaires.

Resumo

Antipsicóticos para dor aguda e crónica em adultos

Introdução

Esta é uma versão atualizada da revisão original Cochrane publicado em Issue 4, 2008. O papel dos antipsicóticos como analgésicos adjuvantes é um assunto controverso de longa data. Neuroleptoanalgesia (corresponde a um estado de quiescência, consciência alterada e a analgesia, produzida pela combinação do uso de um analgésico opioide associado a um antipsicótico), um termo estabelecido para o manejo da dor aguda, mostrou influenciar negativamente o curso da doença e a mortalidade total em pacientes com angina instável. No entanto, antipsicóticos são utilizados no tratamento da dor crônica (por exemplo, cefaleia crônica, fibromialgia e neuropatia diabética). Com antipsicóticos atípicos, uma nova classe de antipsicóticos, há menos efeitos colaterais extrapiramidais e outros benefícios adicionais podem estar disponíveis.

Objetivos

Para avaliar a eficácia analgésica e efeitos adversos dos antipsicóticos na dor aguda ou crônica em adultos.

Métodos de busca

As seguintes bases de dados foram pesquisados: CENTRAL, em A Biblioteca Cochrane (Edição 12, de 12, de 2012); MEDLINE (1966 a 2013/11/01); EMBASE (1980-2013 semana 03) e PsycINFO 1806 e Jan semana 3 2013. Pesquisas foram executados inicialmente em 2007 e novamente em 2011 e 2013.

Critério de seleção

Ensaios clínicos randomizados (ECR), com pacientes adultos, prescritos com qualquer dose de um antipsicótico oral, para dor aguda ou crónica, em que a avaliação subjetiva da dor foi descrita como desfecho primário ou secundário, foram incluídos nesta revisão.

Coleta dos dados e análises

Os dados foram extraídos por dois autores da revisão independentes e os resultados foram comparados às diferenças. Discrepâncias foram resolvidas por discussão. Todos os ensaios foram pontuados qualitativamente de acordo com os métodos estabelecidos no ponto seis do Cochrane Handbook para revisões sistemáticas de intervenções .

Principais resultados

Um total de 770 participantes estiveram envolvidos nos 11 estudos incluídos. Dados de cinco estudos duplo-cego randomizado incluidos demonstram efeitos benéficos dos antipsicóticos no tratamento da dor aguda e crónica. A análise quantitativa destes estudos mostrou uma redução significativa da intensidade média da dor após a administração do antipsicótico em comparação com placebo ou outro componente ativo, diferença de média ponderada (WMD) -1,78 (IC95% -2,71 a -0,85) para variáveis contínuas; e risco relativo (RR) (IC 95% 0,25 a 0,73) 0,43, número necessário para tratar a beneficiar (NNT) 2.6 para os dados dicotômicas. No entanto, o teste para heterogeneidade era significativo para ambos as variáveis contínuas (p = 0,0007) e para variáveis dicotômicas (P = 0,04). Obviamente, isso faz com que o NNT calculado seja menos confiável ​​e se recomenda precaução na interpretação destes resultados.

Os efeitos adversos mais frequentemente relatados foram extrapiramidais (ou seja movimentos involuntários, parkinsonismo e acatisia) e efeitos sedativos.

Conclusão dos autores

Uma pesquisa recente revelou cinco novos estudos, todos excluídos, de modo a manter a avaliação da mesmo forma que a anterior.

Antipsicóticos podem ser utilizados como terapia adjuvante no tratamento de condições dolorosas. No entanto, efeitos colaterais, extrapiramidais e sedativos, têm de ser consideradas antes de introduzir antipsicóticos no tratamento de condições dolorosas.

Resultados de antipsicóticos no tratamento de diferentes condições dolorosas são conflitantes e a maioria dos tamanhos amostrais dos RCTs revisados é pequena. Outros estudos sobre antipsicóticos atípicos em estudos controlados com placebo, duplo-cegos maiores, que incluem a avaliação da dor de maneira padronizada e documentada são necessários.

Notas de tradução

Tradução da Unidade de Medicina Baseada em Evidências da Unesp, Brazil (Marcos André Nogueira Frasson Filho) Contato: portuguese.ebm.unit@gmail.com Translation notes: CD004844

Plain language summary

Analgesic effects of antipsychotics in acute and chronic painful states

Medicines called ‘antipsychotics’, which are used to treat some mental health conditions, are sometimes used to treat chronic pain. A new type of these medicines called 'atypical antipsychotics' is available, with fewer side effects and some additional benefits. The review authors assessed the effect of these medicines on pain and their side effects. Based on 5 out of 11 included trials there were some beneficial effects of antipsychotics in the treatment of acute and chronic pain. Analysis of these studies showed a significant reduction in pain after administration of the antipsychotic compared to placebo or another medicine, however these results were based on small studies and therefore they may be unreliable. It is also important to consider the unwanted effects that these medicines might cause.

Résumé simplifié

Les effets analgésiques des antipsychotiques sur les états douloureux aigus et chroniques

Les médicaments appelés « antipsychotiques », qui sont utilisés pour traiter certains problèmes de santé mentale, sont parfois utilisés pour traiter la douleur chronique. Un nouveau type de ces médicaments appelé « antipsychotique atypique » est disponible, avec moins d'effets secondaires et certains bénéfices supplémentaires. Les auteurs de la revue ont évalué l'effet de ces médicaments sur la douleur et leurs effets secondaires. En se basant sur 5 des 11 essais inclus, ils présentaient certains effets bénéfiques des neuroleptiques pour le traitement de la douleur aiguë et chronique. L'analyse de ces études a montré une réduction significative de la douleur après l'administration de l'antipsychotique par rapport à un placebo ou un autre médicament, mais ces résultats étaient fondés sur des études de petite taille et par conséquent, ils peuvent ne pas être fiables. Il est également important de considérer les effets indésirables que ces médicaments pourraient entraîner.

Notes de traduction

Traduit par: French Cochrane Centre 5th November, 2013
Traduction financée par: Ministère du Travail, de l'Emploi et de la Santé Français

Laički sažetak

Analgetski učinak antipsihotika za liječenje akutne i kronične boli kod odraslih

Lijekovi koji se nazivaju „antipsihotici“, a koji se koriste za liječenje određenih duševnih poremećaja, ponekad se koriste i za liječenje kronične boli. Sada je dostupna nova generacija tih lijekova, koja se naziva „atipični antipsihotici“, i koja ima manje nuspojava i više korisnih učinaka. Autori Cochrane sustavnog pregleda analizirali su učinak tih lijekova na bol i njihove nuspojave. Temeljem 5 od 11 kliničkih studija koje su pronašli u medicinskoj literaturi, zaključeno je da u određenoj mjeri antipsihotici mogu biti korisni u liječenju akutne i kronične boli. Analiza tih kliničkih studija pokazala je značajno smanjenje boli nakon primjene antipsihotika, u usporedbi s placebom ili drugim lijekom. Međutim, ti se rezultati temelje na malim studijama i stoga mogu biti nepouzdani. Također je važno uzeti u obzir moguće nuspojave koje ti lijekovi mogu izazvati prije nego se propišu pacijentima.

Bilješke prijevoda

Prevoditelj:: Croatian Branch of the Italian Cochrane Centre

Resumo para leigos

Efeitos analgésicos de antipsicóticos nos estados de dor aguda e crônica

Medicamentos denominados "antipsicóticos", utilizados para tratar alguns problemas de saúde mental, são por vezes utilizados no tratamento da dor crônica. Um novo tipo dessas medicações, chamados de "antipsicóticos atípicos" está disponível, com menos efeitos colaterais e alguns benefícios adicionais. Os autores da revisão avaliaram o efeito destes medicamentos na dor e seus efeitos colaterais. Com base em 5 dos 11 ensaios incluídos houve alguns efeitos benéficos dos antipsicóticos para o tratamento da dor aguda e crónica. A análise desses estudos demonstrou uma redução significativa na dor após a administração do antipsicótico em comparação com o placebo ou outro medicamento, no entanto, estes resultados foram baseados em estudos pequenos e, portanto, podem não ser confiáveis. Também é importante considerar os efeitos indesejados que estes medicamentos possam causar.

Notas de tradução

Tradução da Unidade de Medicina Baseada em Evidências da Unesp, Brazil (Marcos André Nogueira Frasson Filho) Contato: portuguese.ebm.unit@gmail.com Translation notes: CD004844

Background

This review is an update of a previously published review in the Cochrane Database of Systematic Reviews (2008, Issue 4).

Antipsychotics (also called neuroleptics) can be classified according to their chemical structure into tricyclic antipsychotics (phenothiazines, thioxanthenes), butyrophenones, substituted benzamides and other chemical substances (dichlorphenyl-piperazinyl-chiloninones, diphenylbutylpiperidines, benzisoxazoles, benzisothiazylpiperazines, phenylpiperidines). Atypical antipsychotics differ from classical antipsychotics, or 'first generation antipsychotics', in the extrapyramidal side effects, effectiveness in negative symptomatology, and lower prolactin elevations with comparable antipsychotic efficacy. Classical antipsychotics have a predominant dopamine D2 antagonism, whereas the atypical antipsychotics also address other neurotransmitter systems, for example the serotonin system. In clinical practice cardiovascular side effects, especially a prolonged QTc, have to be kept in mind when treating patients with antipsychotics.

The therapeutic effects of antipsychotics make them a potential choice as drugs in the treatment of pain. To date the role of classic antipsychotics such as adjuvant analgesics has been a subject of longstanding controversy. Their clinical usefulness in the management of pain is questioned (Patt 1994). Neuroleptanalgesia (that is a state of quiescence, altered awareness, and analgesia produced by a combination of taking an opioid analgesic and an antipsychotic) as an established term for the management of acute pain was shown to negatively influence disease course and total mortality in unstable angina patients (Burduk 2000).

Antipsychotics are also used in a variety of different chronic pain states, from cancer pain (Bloomfield 1964; Breitbart 1998; Khojainova 2002) to chronic non-cancer pain (Merskey 1997) as in chronic headache or chronic refractory headache (Hakkarainen 1977; Lu 2000; Silberstein 2002), fibromyalgia (Kiser 2001), musculoskeletal pain (Bloomfield 1964), low back pain (Bloomfield 1964; Jermyn 2001), chronic pain in older patients (Feinberg 2000), pain in AIDS (Breitbart 1998), post-herpes zoster (Gobel 1997; Montilla 1963), chronic facial pain (Lechin 1989; Peschen-Rosin 2002), and diabetic neuropathia (Gomez-Perez 1985).

In a meta-analysis on the analgesic potency of antipsychotics by Nix and colleagues (Nix 1998) only 10 out of 15 studies with a higher statistical power described a possible analgesic effect. None of the studies identified could differentiate between the effects of analgesia and sedation of the drugs used.

The way antipsychotics work to relieve pain is still under debate and may differ between different agents. For some pain syndromes (for example migraine) antidopaminergic properties may mediate the analgesic effects. Also, the serotonin antagonism of some antipsychotic agents is believed to mediate the analgesic effects (Schreiber 1999). Additionally, for some antipsychotics (for example olanzapine) their agonistic activity at alpha2-adrenoceptors is believed to mediate analgesic effects (Silberstein 2002).

Besides discussions about the potential of antipsychotics to be used as analgesics, a potent antinociceptive effect has been shown for risperidone, an atypical antipsychotic, in an in vivo animal pain model (that is the tail-flick assay). Further evaluation of risperidone with selective opioid antagonists revealed the involvement of µ1-, µ2-, and kappa1-opioids and, to a lesser extent, delta-opioid mechanisms. For olanzapine the alpha2-adrenoceptors and to a lesser extent the opioid and serotonergic receptors are involved in the antinociception (Schreiber 1999).

With the arrival of atypical antipsychotics, a new class of antipsychotics, fewer extrapyramidal side effects and additional benefits are now available. These new treatments were not included in a meta-analysis of reports on the analgesic effects of antipsychotics performed by Nix 1998. Therefore, a new meta-analysis is needed to address the question of evidence based pain therapy with antipsychotics.

Objectives

To assess the analgesic efficacy and adverse effects of antipsychotics in acute or chronic pain in adults.

Methods

Criteria for considering studies for this review

Types of studies

We included randomised controlled trials (RCTs) which were double blinded and which investigated the analgesic effects of antipsychotics as monotherapy or add-on treatment in patients with acute or chronic pain, if pain assessment was either the primary or a secondary outcome. Reports were excluded if they were studies which were non-randomised, studies of experimental pain, case reports, clinical observations (open studies) or studies of antipsychotics used to treat pain produced by other drugs.

Types of participants

Randomised controlled trials (RCTs) of adult patients of either gender who had acute or chronic pain, or both, of all degrees of severity, were included in this review.

Types of interventions

Any form of antipsychotic treatment (at any dose) listed below compared with no treatment, placebo, or other pain relieving treatment (for example non-steroidal anti-inflammatory drugs (NSAIDs), antidepressants, anticonvulsants, opiates).

Antipsychotic agents or neuroleptics:
  • amisulpride,

  • amoxapine,

  • chlormethiazole,

  • clopenthixol,

  • chlorpiprazine,

  • chlorpromazine,

  • chlorprothixene,

  • cloxazepine,

  • clozapine,

  • distraneurine,

  • dixyrazine,

  • droperidol

  • chlorpromazine,

  • flupentixol decanoate,

  • fluphenazine,

  • haloperidol,

  • levomepromazine,

  • loxapine,

  • melperone hydrochloride,

  • methotrimeprazine,

  • olanzapine,

  • oxilapine,

  • perphenazine,

  • pimozide,

  • prochlorperazine

  • prothipendyl hydrochloride,

  • quetiapine,

  • risperidone,

  • sulpiride,

  • thioridazine,

  • tiapride,

  • tisercin,

  • trifluoroperazine,

  • ziprsasidone,

  • zotepine,

  • zuclopenthixol.

For the update of this review in January 2013 we included two additional antipsychotics, namely droperidol and prochlorperazine, in our search strategy.

Types of outcome measures

Primary outcomes

The primary outcome measure for this review was the reduction in pain intensity as measured by a visual analogue scale (VAS), self reported global scale, verbal rating scale, numerical rating scale or categorical pain relief scale, and self reported pain relief. We used the effectiveness measures after the longest reported duration of treatment. We excluded studies which did not quantify pain using a scale. We included patient reported pain data, and excluded trials only reporting physician and carer pain assessment.

Secondary outcomes

An assessment of the frequency and severity of the commonly expected adverse effects was undertaken. Adverse effects were classified as minor if they were reported by a participant who continued with the medication and completed the trial. A major adverse effect was defined as one that caused the participant to withdraw from the study. Side effect data are recorded in Table 1.

Table 1. Side effects
Author/YearSubstanceType of side effectPercentage
Ginsberg 1983TiaprideDrowsiness (moderate to mild), mild gastric intolerance38.1%
Lechin 1989PimozidePhysical and mental retardation, hand tremors, memory impairment, involuntary movements during sleep (jerkings) and slight Parkinson's disease manifestations83.3%
Langemark 1994SulpirideSedation, depression, nausea, sleep disturbance, increased dreaming, uneasiness, weight gain, obstipation, amenorrhoea, galactorrhoea, impotence, restless legs, micturation difficulties, polyuria, accomodation difficulties, dry mouth, orthostatic hypotensionauthor only provided incidences, at least 34%
Roux 1983Tiaprideno side effects reported--
Johnston 1972ThioridazineNo untoward effects were observed or reported at any time during the study--
Davidsen 1979LevomepromazineDry mouth59%
Graff-Radford 2000FluphenazineSleepiness, dry mouth--
Zitman 1991FlupentixolDry mouth--
Judkins 1982HaloperidolNo serious side effects were observed, dry mouth--
Bussone 1980TiaprideNo extrapyramidal, neuroendocrine or neurovegetative side effects were observed--
Honkaniemi 2006HaloperidolMotor agitation, sedation, hyperventilation and shortness of breath80%
Richman 2002DroperidolSedation, akathisiaSedation: 6.7% (droperidol) vs. 13.4% (meperidine); akathisia 13.3% (only droperidol reported)
Additional outcomes
  • Attrition, the numbers of participants withdrawing before completion of the study in an intervention versus placebo study and an intervention versus other treatment study due to non-compliance, adverse effects or death

  • Measures of satisfaction or patient preference (if reported)

  • Assessment of quality of life (if reported)

Search methods for identification of studies

Electronic searches

This search was run for the original review in October 2007 and subsequent searches were run in 2011 and January 2013.

For the identification of studies to be included or considered for this review, the following databases were searched:

  • Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (2012, Issue 12);

  • MEDLINE (1966 to January 2013);

  • EMBASE (1989 to January 2013);

  • PsycINFO (1806 to January 2013).

Detailed search strategies were developed for each database searched and the MEDLINE search strategy from the original 2007 search is given in Appendix 1; for other search strategies please see Appendix 2 and the search strategies used for the 2013 updated searches can be found in Appendix 3. The searches attempted to identify all relevant studies irrespective of language. Non-English papers would be assessed and translated, if necessary, with the assistance of a native speaker.

Searching other resources

We checked reference lists from retrieved trials for additional studies. We also sought relevant studies cited in reviews identified by searching the Cochrane Database of Systematic Reviews (CDSR) and the Database of Abstracts of Reviews and Effectiveness (DARE).

We contacted the corresponding authors of the identified articles and experts in the field for additional studies. Furthermore, we sent letters requesting information about published or unpublished trials to pharmaceutical companies which manufacture antipsychotics (Sanofi-Synthelabo: amisulpride, fluphenazine, sulpiride, tiapride; Lundbeck: chlorprothixene, flupentixol decanoate, melperone, sertindole, zuclopenthixol; Novartis: clozapine, thioridazine; Eli Lilly: olanzapine; AstraZeneca: quetiapine; Janssen-Cilag: haloperidol, pimozide, risperidone; Asta Medica: prothipendyl hydrochloride; Knoll Ltd: zotepine; Pfizer: ziprasidone; Gerot: levomepromazine; UCB-Pharma: dixyrazine).

Data collection and analysis

Study selection

Two review authors (MA and MO) independently screened the titles and abstracts of all the references retrieved by the original search strategy. Two other authors (SS and TS) independently screened the titles and abstracts of all references retrieved by the search strategy for this update. The full text versions of relevant studies were retrieved by BW and were assessed independently by the authors (MA, MO, TS and SS) to determine whether they met the inclusion criteria. Disagreements were resolved by discussion among the four authors mentioned above.

Assessment of quality

Trials which met the inclusion criteria were graded independently for methodological quality and assessed for internal validity using the Oxford Quality Scale score (Jadad 1996):

  • randomisation (1 = yes; 0 = no);

  • method and description of randomisation (0 = not described; 1 = described and adequate; -1 = described, but not adequate);

  • double blinding (1 = yes; 0 = no);

  • method and description of double blinding (0 = not described; 1 = described and adequate; -1 = described, but not adequate);

  • sufficient information about loss to follow-up (1 = yes; 0 = no).

Each study was allocated a score of between one to five points. Because the inclusion criteria for this review required trials to be randomised, the minimum quality score was one. Higher scores indicated a higher quality of conducting or reporting, or both, of the trial. No trial that scored '0' met the inclusion criteria, the minimum score calculated was two.

Data extraction

The following data items were extracted from each of the included studies, where available:

  • trial characteristics (methods, duration, interventions);

  • patient characteristics (age, gender, type of pain condition);

  • trial results (patient reported pain intensity or pain relief);

  • adverse effects (major and minor);

  • study withdrawals (due to non-compliance, adverse effects or death);

  • measures of satisfaction or patient preference (if reported); and

  • assessment of quality of life (if reported).

Data were extracted on to a standard form by two review authors working independently. Due to possible carry-over effects, only the first phase of cross-over studies was used.

Analysis

Statistical testing of heterogeneity between the trials was carried out by one author (EP) using RevMan Analyses 1.0.3 in Meta-View 4.2.8 (RevMan 2012). Results from the trials were combined using a fixed-effect model to calculate relative risks (RR) with 95% confidence intervals (CI) for dichotomous data and weighted mean differences (WMD) for continuous data.

If enough data were available, the number needed to treat to benefit (NNT) was calculated.

Subgroup analyses

The quality of the included trials was used in exploring any significant statistical heterogeneity between them. Cut-off levels for the subgroup analysis values that were used were 'greater or equal to three' or 'less than or equal to two'.

Results

Description of studies

Study selection

The search for this update (from October 2007 to January 2013) resulted in 2083 hits. After screening of the titles and abstracts five potentially relevant studies were identified. Unfortunately, these studies had to be excluded because of the following reasons.

  • The study by Hill et al (Hill 2008) compared the efficacy of the antipsychotic to another antipsychotic (that is droperidol).

  • The study by Friedman et al (Friedman 2008) compared the efficacy of the antipsychotic to metoclopramide.

  • The study by Miller et al (Miller 2009) compared the efficacy of the antipsychotic to octreotide.

  • The study by Kostic et al (Kostic 2010) compared a combination of prochlorperazin with diphenhydramine to sumatriptan.

  • The study by Potvin et al (Potvin 2012) did not use pain as the primary outcome parameter.

The original search strategy, run in October 2007, resulted in 1908 hits. After screening of the titles and abstracts, 56 potentially relevant studies were identified. Forty-one studies were excluded (see 'Characteristics of excluded studies' table). In short, 39 studies did not meet the quality criteria as assessed by the Oxford Quality Scale. Two high-quality studies (Brousseau 2004; Weaver 2004;) were excluded because they reported the efficacy of an antipsychotic on headache in children and adolescents (Brousseau 2004) and compared two antipsychotics (droperidol vs. prochlorperazine) without the use of a placebo (Weaver 2004). Hence, 15 studies were considered for inclusion in this review. Two of these studies could not be assessed because a translation into English was not available (Govorin 1990; Lepola 1984). For one further study the authors could not be identified, and it was therefore excluded (Anon 1986).

Overall 12 RCTs of nine different antipsychotics were considered eligible (Bussone 1980; Davidsen 1979; Ginsberg 1983; Graff-Radford 2000; Honkaniemi 2006; Johnston 1972; Judkins 1982; Langemark 1994; Lechin 1989; Richman 2002a; Roux 1983; Zitman 1991) (n = 772) for inclusion in the review, please see the 'Characteristics of included studies' table for full details of each included study. All included studies were clinic based and single centered, with one (Lechin 1989) explicitly stating the inclusion of outpatients. They were conducted at the departments for neurology (n = 4) (Bussone 1980; Honkaniemi 2006; Langemark 1994; Lechin 1989), anaesthesiology (n = 2) (Graff-Radford 2000; Judkins 1982), psychiatry (n = 1) (Zitman 1992), neurosurgery (n = 1) (Roux 1983), oncology (n = 1) (Johnston 1972) and the emergency department (n = 2) (Davidsen 1979; Richman 2002a). The site of the remaining study (Ginsberg 1983) could not be specified. The sample size ranged from 29 to 316 participants. Most trials were limited by their small sample size. Only one trial included more than 200 participants (Davidsen 1979). Eight studies were placebo-controlled and were considered for quantitative analysis. Data from six studies could not be included in the quantitative analysis because of the following reasons.

  • Two studies compared the efficacy of the antipsychotic to an opioid (Davidsen 1979) or a selective serotonin reuptake inhibitor (SSRI) (Langemark 1994).

  • One study only reported on the occurrence of headaches following an intervention (Roux 1983).

  • One study did not provide information about the duration of treatment (Bussone 1980).

  • The work of Johnston 1972 fulfilled the inclusion criteria, but due to missing data on variability, the study could not be included in the final analyses. Similarly, the study by Judkins 1982 had to be excluded due to missing data on the mean and variability of the selected outcome variables.

Risk of bias is shown in Figure 1 for each included study.

Figure 1.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

For the meta-analyses, the primary outcome variable was the difference in mean in the treatment and placebo groups (after - baseline) and therefore reflected how much the VAS score could be reduced by the treatment. Additionally, the meta-analysis was performed for the mean outcome VAS score following treatment in both groups. For the dichotomous event, feeling pain or no pain after treatment, the RR indicated the chance of having pain after receiving the intervention, an absolute risk reduction (ARR) < 1 means that the chance of having pain after the intervention is smaller in the treatment group than in the control group. The study authors were contacted to provide missing data, if necessary. Standard errors were converted into standard deviations. If the standard deviation of the difference in mean was not given, but the standard deviation from baseline and after treatment was given, imputation strategies were used (Higgins 2011). If values for the mean or standard deviation were not mentioned in the text, but were displayed in a figure, values were taken from the figure.

Study design

Nine of the included studies had a parallel design and three had a cross-over design. Some trials had more than two arms and made more than one comparison.

Outcomes

Pain was patient reported in 12 trials. In one study information on pain was provided by the patients' weekly ratings (Johnston 1972). In six trials pain was reported using a pain diary (Bussone 1980; Ginsberg 1983; Graff-Radford 2000; Langemark 1994; Lechin 1989; Zitman 1991). Three trials documented the analgesic requirements of the patients on a numeric VAS (Judkins 1982; Richman 2002a; Honkaniemi 2006). Two trials simply reported on the mere occurrence of pain (Davidsen 1979; Roux 1983).

Study methods

All 12 included studies were conducted in a double-blind fashion. Eight trials compared an antipsychotic or a combination of analgesic and antipsychotic to placebo and three studies compared an antipsychotic or a combination of analgesic and antipsychotic to treatment with an active compound (that is antidepressants, antiepileptics or analgesics).

Antipsychotics

Trials using the following antipsychotics were found:

  • Five with tricyclic antipsychotics (flupentixol, fluphenazine, thioridazine, levomepromazine);

  • four with butyrophenones (droperidol, haloperidol);

  • three with benzamides (sulpiride, tiapride, pimozide).

Patient conditions

The underlying conditions studied were as follows:

  • somatoform pain disorder, one study;

  • post-herpetic neuralgia, one study;

  • acute (migraine) headache, two studies;

  • pain in terminal cancer, one study;

  • postoperative pain, one study;

  • trigeminal neuralgia, one study;

  • acute rheumatic pain, one study;

  • chronic tension-type headache, two studies;

  • post-rachiocentesis headache, one study; and

  • acute myocardial infarction, one study.

Details of these eligible reports are provided in the 'Characteristics of included studies' table.

Risk of bias in included studies

Each study was scored independently for quality by two of the review authors (MA and MO) using the three-item Oxford Quality Scale (Jadad 1996). The scores for individual trials are reported in the notes section of the 'Characteristics of included studies' table. The median quality score for the placebo-controlled studies was three (all trials scored three), and for the active control studies it was also three (range three to four).

Effects of interventions

Overall 12 RCTs of nine different antipsychotics were considered eligible (Bussone 1980; Davidsen 1979; Ginsberg 1983; Graff-Radford 2000; Honkaniemi 2006; Johnston 1972; Judkins 1982; Langemark 1994; Lechin 1989; Richman 2002a; Roux 1983; Zitman 1991) (total n = 743) for inclusion in the review. Forty studies were excluded and are listed in the 'Characteristics of excluded studies' table.

Tricyclic antipsychotics

Four trials (Davidsen 1979; Graff-Radford 2000; Johnston 1972; Zitman 1991), with a total of 449 participants, studied the effects of tricyclic antipsychotics in different painful disorders. These trials studied the effect of tricyclic antipsychotics in:

  1. pain following myocardial infarction (Davidsen 1979),

  2. pain due to terminal cancer (Johnston 1972),

  3. somatoform pain disorder (Zitman 1991), and

  4. post-herpetic neuralgias (Graff-Radford 2000).

The description of the study results is given below.

Tricyclic antipsychotics versus placebo

One study indicated only a small positive effect of 75 mg thioridazine daily compared to placebo concerning global improvement and pain in terminal cancer patients (P < 0.1) (Johnston 1972). The study of Graff-Radford et al had four arms (amitriptyline, amitriptyline + fluphenazine, fluphenazine, and placebo). For quantitative analysis we only included data from the fluphenazine and the placebo arms (Graff-Radford 2000).

Tricyclic antipsychotics versus other active treatment

Three studies compared tricyclic antipsychotics to other active treatments, including amitriptyline (a tricyclic antidepressant) (Graff-Radford 2000; Zitman 1991) and pethidine (an opioid) (Davidsen 1979).

Administration of levomepromazine proved to significantly reduce the recurrence of pain within the first 72 hours after an acute myocardial infarction compared to treatment with pethidine (P < 0.05) (Davidsen 1979). In the case of post-herpetic neuralgia the decrease of pain in patients receiving fluphenazine did not reach statistical significance. Combination of the antipsychotic with a tricyclic antidepressant (that is amitriptyline) and comparison with treatment with amitriptyline alone failed to produce a significant advantage using fluphenazine: mean difference (MD) 0.54 (95% CI -1.49 to 2.57) (Graff-Radford 2000). In another study, patients with a somatoform pain disorder receiving 75 mg amitriptyline or 75 mg amitriptyline plus 3 mg flupentixol experienced significantly less pain during the treatment. Yet, the comparison of pain reduction in both groups did not reveal a statistically significant MD (MD -0.60, 95% CI -2.10 to 0.90) (Zitman 1991).

Butyrophenones

Three placebo-controlled RCTs (Honkaniemi 2006; Judkins 1982; Richman 2002a), with a total of 110 participants, studied the effects of butyrophenones on postoperative pain (Judkins 1982) and acute migraine headache (Honkaniemi 2006; Richman 2002a).

In the case of postoperative pain two different dosages of haloperidol (5 and 10 mg orally) were compared against placebo as premedication before major abdominal surgery (Judkins 1982). VAS scores for pain at 24 hours after surgery did not differ significantly between the three groups of participants. Only a significant reduction of postoperative emesis was found in both groups treated with haloperidol. In contrast, treatment of acute migraine headache with 5 mg intravenous haloperidol was shown to be significantly superior to placebo (MD -4.05, 95% CI -5.61 to -2.49) (Honkaniemi 2006). Another study on acute migraine compared 2.5mg intramuscular droperidol with 1.5mg/kg meperidine and failed to detect a significant difference regarding post-treatment pain intensity (VAS) (47 vs. 37 mm, p=.033) (Richman 2002a).

Benzamides

Five double-blind trials with a total of 240 participants, two of them placebo-controlled (Bussone 1980; Roux 1983), studied the effects of benzamides on different types of headache (Bussone 1980; Langemark 1994; Roux 1983), trigeminal neuralgia (Lechin 1989) and acute rheumatic pain (Ginsberg 1983).

In the case of chronic tension-type headache tiapride was compared with placebo (Bussone 1980) and sulpiride was compared with another active component, that is paroxetine an SSRI (Langemark 1994). It seemed noteworthy that five participants in the group receiving sulpiride dropped out during the study due to intolerable side effects (Langemark 1994), see Table 1 for further details.

Benzamides versus placebo

The effect of intravenous tiapride (dosage 200 mg) following rachiocentesis was studied in a small sample (n = 30) (Roux 1983). The authors only reported the percentage of patients who experienced pain within 48 hours after rachiocentesis, but did not provide any further details (for example pain severity or associated symptoms). When compared to the placebo, tiapride led to a reduction in the occurrence of headaches. In detail, 86.7% of patients who had received tiapride before the rachiocentesis and 46.6% of patients who had received placebo did not report headaches within 48 hours following the procedure. These results were statistically significant (P < 0.01).

An Italian group reported on the efficacy of 300 mg tiapride administered orally on chronic tension-type headache, but failed to provide any information on the duration of the treatment conducted in the study (Bussone 1980). Forty per cent of the patients treated with tiapride were complete responders compared to no responders with placebo (Bussone 1980).

Benzamides versus other active treatment

Sulpiride (400 mg daily) and paroxetine (30 mg daily), an SSRI, were compared in a group of 50 patients suffering from chronic tension-type headache in a cross-over conditional-response design (Langemark 1994). Each treatment period lasted eight weeks. Patients recorded their pain in headache diaries. Total pain scores differed significantly between groups (P = 0.03) favouring treatment with the antipsychotic.

Pimozide (12 mg daily) and carbamazepine (1200 mg daily), antiepileptic drugs established in the treatment of neuralgic pain, were tested in the treatment of pain due to trigeminal neuralgia in 48 participants, using a cross-over design (Lechin 1989). During both treatment phases pimozide proved to be superior to carbamazepine regarding total trigeminal neuralgia pain scores (P < 0.01) (MD -4.11, 95% CI -8.08 to -0.14).

In the case of acute rheumatic pain tiapride (100 mg daily) and glafenine (200 mg daily), an anthranilic acid derivative with analgesic properties, were compared during a 14-day double-blind trial (Ginsberg 1983). Tiapride was significantly superior to glafenine regarding the time delay until the disappearance of the pain (P < 0.05). Concerning pain reduction there was a trend favouring the antipsychotic (RR 0.73, 95% CI 0.37 to 1.44), though it failed to show statistical significance. A separate analysis according to the sex of patients did not reveal any significant differences (Ginsberg 1983).

Five of these trials permitted a quantitative analysis of the study data according to our protocol. The results of these analyses are available in Analysis 1.1, Analysis 1.2 and Analysis 1.3.

Discussion

This systematic review revealed a small number (n = 12) of small-sized clinical trials (total n = 772) that compared the analgesic effects of antipsychotics to placebo or active compounds in a randomised double-blind fashion.

There are some preclinical studies in humans that link the dopaminergic system with pain. In one study an inverse correlation of pain threshold and the response criterion with the D2/D3 binding potential in the right putamen was found (Pertovaara 2004). This finding is supported by a number of animal studies which have suggested that dopamine is involved in the regulation of nociception. However, the data are contradictory as dopamine agonists have been shown to produce either antinociception (Shimizu 2004) or hyperalgesia (Paalzow 1992).

It appears reasonable to further investigate the analgesic effect of various antipsychotics in different pain syndromes. Thus, we describe the effects of different antipsychotics in the following painful conditions.

Headaches

The effects of antipsychotics have been studied in the treatment of acute migraine headache (Honkaniemi 2006; Richman 2002a), chronic tension-type headache (Bussone 1980; Langemark 1994) and headaches following rachiocentesis (Roux 1983) using randomised double-blind designs. All but one trial (Richman 2002a) demonstrated statistically significant positive results for antipsychotics, that is haloperidol, sulpirid and tiaprid. It seems noteworthy that administration of tiaprid did not lead to a greater reduction of headache intensity, but led to a faster amelioration of headache following rachiocentesis (Roux 1983).

Neuralgic pain

Treatment of patients with neuralgic pain (post-herpetic neuralgia (Graff-Radford 2000) and trigeminal neuralgia (Lechin 1989)) delivered both positive and negative results. Fluphenazine, used in the case of post-herpetic neuralgia, did not prove to be superior to amitriptyline, a tricyclic antidepressant (Graff-Radford 2000). On the other hand, a study with patients suffering from trigeminal neuralgia appeared to show that pimozide led to a significantly greater reduction of pain in a double-blind cross-over study (Lechin 1989).

Other painful conditions

The effects on several other painful conditions have been studied in double-blind RCTs. We could only identify a single study for each condition, which met our inclusion criteria. This is one of the limitations of the data presented here. In summary, we can say that only one study reported a statistically significant positive effect on pain, that is pain following an acute myocardial infarction (Davidsen 1979). Intriguingly, that study turned out to hold the largest sample (n = 316) of all studies included. Trials on somatoform pain disorders (Zitman 1991), postoperative pain (Judkins 1982) and acute rheumatic pain (Ginsberg 1983) failed to deliver significant results favouring the treatment with antipsychotics.

Antipsychotics and acute pain

Four of six studies on acute painful conditions that were reviewed here (Ginsberg 1983; Judkins 1982; Richman 2002a; Roux 1983) did not find significant positive results for antipsychotics concerning reduction of pain intensity. One study (Davidsen 1979), using a large sample of patients, reported a statistically significant reduction of pain after an acute myocardial infarction. The data of Honkaniemi and colleagues demonstrated an excellent response of acute migraine headache to the administration of haloperidol (Honkaniemi 2006). In addition, after the administration of tiaprid post-rachiocentesis headache disappeared more quickly when compared to placebo, although pain reduction was not greater than in patients who received placebo (Roux 1983).

Antipsychotics and chronic pain

Six studies included in this review focused on the management of chronic pain conditions. In the case of chronic tension-type headaches two studies reported beneficial effects for patients treated with antipsychotics when compared to placebo or another active component (Bussone 1980; Langemark 1994). Results concerning neuralgic pain turned out to be both negative (Graff-Radford 2000) and positive (Lechin 1989). In the latter study the antipsychotic was more efficient than carbamazepine, a well-established drug in the treatment of neuralgias. Treatment of a somatoform (that is physical symptoms that mimic disease or injury for which there is no identifiable physical cause) pain disorder with flupentixol (Zitman 1991) and pain in terminal cancer patients with thioridazine (Johnston 1972) was not reported to be superior to placebo or another treatment (Zitman 1991).

Summarising the results of all 11 included RCTs we found a positive effect in painful conditions in six trials, whereas five trials failed to report any analgesic effect of the antipsychotics studied. Five trials proved eligible for a meta-analysis. We next set out to perform quantitative analyses of studies on acute (n = 2) and chronic pain (n = 3) separately, but this does not seem reasonable to us due to the small number and tremendous clinical heterogeneity of the studies. In addition, the data reviewed here have further limitations as most trials studied small samples of patients and only one included more than 200 participants. Moreover, pain assessment varied among the different protocols. Some studies only reported on the (re-)occurrence of pain, which is, from our point of view, not sufficient to assess the whole effect on painful states.

Thus, in the present review the evidence of analgesic properties of antipsychotics can only be described relying on each single study. From a clinical point of view further research on analgesic properties of antipsychotics is indicated in more RCTs. Since nowadays atypical antipsychotics, which are known to produce lesser extrapyramidal side effects, are available, this new group of antipsychotics clearly needs to be studied regarding their analgesic potency.

In this update we also added antipsychotics (that is prochlorperazine and droperidol) to our search strategy. Nevertheless we could not include any new studies. One of the excluded studies (Hill 2008) concluded that olanzapine, a newer atypical antipsychotic, was equally potent to droperidol, an older antipsychotic, to relieve headaches. This finding should encourage researchers to further study the efficacy of newer antipsychotic agents in the treatment of pain disorders.

Authors' conclusions

Implications for practice

Antipsychotics could be used as add-on therapy in the treatment of painful conditions, as a possibility for treatment-resistant pain. Adverse effects of typical antipsychotics, especially the extrapyramidal and sedating effects, have to be considered in the decision algorithm for the use of antipsychotics in painful conditions. Nevertheless, the significance of these results is limited due to the heterogeneity of the included studies.

Implications for research

The results for antipsychotics in the treatment of different painful conditions are heterogeneous and most sample sizes in the reviewed randomised double-blind studies are small. However, further studies are warranted on atypical antipsychotics with fewer side effects than the classical antipsychotics, in larger double-blind placebo-controlled studies that include standardised pain assessment.

Acknowledgements

We would like to thank Tiina Saarto for data extraction and translation of manuscripts.

Data and analyses

Download statistical data

Comparison 1. Reduction in pain intensity
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Acute and chronic pain continuous data - difference posttreatment minus baseline4148Mean Difference (IV, Fixed, 95% CI)-2.16 [-1.00, -1.32]
1.1 acute140Mean Difference (IV, Fixed, 95% CI)-4.52 [-5.88, -3.16]
1.2 chronic3108Mean Difference (IV, Fixed, 95% CI)-0.71 [-1.78, 0.35]
2 Acute pain dichotomous data282Risk Ratio (M-H, Fixed, 95% CI)0.43 [0.25, 0.73]
2.1 acute282Risk Ratio (M-H, Fixed, 95% CI)0.43 [0.25, 0.73]
3 Acute and chronic pain continuous data - mean after treatment4 Mean Difference (IV, Fixed, 95% CI)Totals not selected
3.1 acute1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
3.2 chronic3 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
Analysis 1.1.

Comparison 1 Reduction in pain intensity, Outcome 1 Acute and chronic pain continuous data - difference posttreatment minus baseline.

Analysis 1.2.

Comparison 1 Reduction in pain intensity, Outcome 2 Acute pain dichotomous data.

Analysis 1.3.

Comparison 1 Reduction in pain intensity, Outcome 3 Acute and chronic pain continuous data - mean after treatment.

Appendices

Appendix 1. MEDLINE search strategy

A , B, C combined with AND

A. Neuroleptic/antipsychotic drugs (combined with OR)
Free Term
neurolept*, antipsychotic*, Amisulpride*, Chormethiazole*, Clomethiazole*, Distraneurin*, Chlorpromazin*, Aminazine*, Chlorazine*, Chlordelazine*, Contomin*, Fenactil*, Largactil*, Propaphenin*, Thorazine*, Flupenthixol decanoate*, Emergil*, Fluanxol*, Flupentixol*, alphaFlupenthixol*, cisFlupenthixol*, Fluphenazin*, Fluphenazine decanoate*, Flufenazin*, Fluphenazine Hydrochloride*, Lyogen*, Prolixin*, Haloperidol*, Haldol*, Levomepromazin*, Levomeprazin*, Levopromazine*, Tisercin*, Tizercine*, Tizertsin*, Methotrimeprazine*, Loxapine*, Loxapinsuccinate*, Oxilapine*, Cloxazepine*, Loxapine Monohydrochloride*, Loxipine Maleate*, Loxipine Succinate*, Loxitane*, Asendin*, Desmethylloxapine*, Amoxapine*, Olanzapine*, Perphenazine*, Chlorpiprazine*, Perfenazine*, Trilafonor*, Pimozide*, Prothipendyl*, Quetiapine*, Fumarate*, Risperidone*, Risperidal*, Sulpiride*, Dogmatil*, Eglonyl*, Sulperide*, Thioridazine*, Meleril*, Mellaril*, Melleril*, Melleryl*, Sonapax*, Thioridazine Hydrochloride*, Tiaprid*, Tiapridal*, Trifluoperazine Hydrochloride*, Trifluoroperazine*, Triftazin*, Stelazine*, Trifluperazine*, Tripfluoperazine Hydrochloride*, Cisordinol*, Zuclopenthixol*, Clopenthixol*, Clozapine*, Melperone hydrochloride*, Ziprasidone*, Zotemine*
MeSH
Pimozide, Perphenazine, explode Loxapine, Methotrimeprazine, Haloperidol, Fluphenazine, Flupenthixol, Chlorpromazine, Chlormethiazole, Antipsychotic-Agents, Clopenthixol, Trifluoperazine, Tiapride, Thioridazine, Sulpiride, Risperidone, Fumarates

B. Pain (combined with OR)
Free Term
pain*
MeSH
explode Pain

C. RCT-Filter
See Cochrane Handbook of Systematic Review of Interventions (Higgins 2011)

Appendix 2. Additional search strategies

Database searchedSearch strategy
EMBASE A , B, C combined with AND

A. Neuroleptic/antipsychotic drugs (combined with OR)
Free Term
neurolept*, antipsychotic*
EMTREE
Neuroleptanalgesia
explode neuroleptic-agent

B.Pain (combined with OR)
Free Term
pain*
EMTREE
explode Pain

C.RCT-Filter (combined with OR)
Free Term
random* in ab,ti
cross?over* in ab,ti
factorial* in ab,ti
placebo* in ab,ti
volunteer* in ab,ti
(singl* or doubl* or trebl* or tripl*) near (blind* or mask*) in ab,ti
EMTREE
randomized-controlled-trial, randomization, controlled-study, multicenter-study, phase-3-clinical-trial, phase-4-clinical-trial, double-blind-procedure, single-blind-procedure
PSYNDEX A , B, C combined with AND

A. Neuroleptic/antipsychotic drugs (combined with OR)
Free Term
neurolept*, antipsychoti*, Amisulpride*, Chormethiazole*, Clomethiazole*, Distraneurin*, Chlorpromazin*, Aminazine*, Chlorazine*, Chlordelazine*, Contomin*, Fenactil*, Largactil*, Propaphenin*, Thorazine*, Flupenthixol decanoate*, Emergil*, Fluanxol*, Flupentixol*, alphaFlupenthixol*, cisFlupenthixol*, Fluphenazin*, Fluphenazine decanoate*, Flufenazin*, Fluphenazine Hydrochloride*, Lyogen*, Prolixin*, Haloperidol*, Haldol*, Levomepromazin*, Levomeprazin*, Levopromazine*, Tisercin*, Tizercine*, Tizertsin*, Methotrimeprazine*, Loxapine*, Loxapinsuccinate*, Oxilapine*, Cloxazepine*, Loxapine Monohydrochloride*, Loxipine Maleate*, Loxipine Succinate*, Loxitane*, Asendin*, Desmethylloxapine*, Amoxapine*, Olanzapine*, Perphenazine*, Chlorpiprazine*, Perfenazine*, Trilafonor*, Pimozide*, Prothipendyl*, Quetiapine*, Fumarate*, Risperidone*, Risperidal*, Sulpiride*, Dogmatil*, Eglonyl*, Sulperide*, Thioridazine*, Meleril*, Mellaril*, Melleril*, Melleryl*, Sonapax*, Thioridazine Hydrochloride*, Tiaprid*, Tiapridal*, Trifluoperazine Hydrochloride*, Trifluoroperazine*, Triftazin*, Stelazine*, Trifluperazine*, Tripfluoperazine Hydrochloride*, Cisordinol*, Zuclopenthixol*, Clopenthixol*
Thesaurus
Explode Neuroleptic-Drugs

B. Pain (combined with OR)
Free Term
pain*
schmerz*
Thesaurus
explode Pain

C. RCT-Filter (combined with OR)
placebo*
random*
control*
kontroll*
prospectiv*
prospekti*
volunteer*
(clin* near trial*)
(klin* near fall*)
(compar* near stud*)
(vergleich* near stud*)
(singl* or doubl* or trebl* or tripl*) near (blind* or mask*)
PsycINFO A , B, C combined with AND

A. Neuroleptic/antipsychotic drugs (combined with OR)
Free Term
neurolept*, antipsychotic*, Amisulpride*, Chormethiazole*, Clomethiazole*, Distraneurin*, Chlorpromazin*, Aminazine*, Chlorazine*, Chlordelazine*, Contomin*, Fenactil*, Largactil*, Propaphenin*, Thorazine*, Flupenthixol decanoate*, Emergil*, Fluanxol*, Flupentixol*, alphaFlupenthixol*, cisFlupenthixol*, Fluphenazin*, Fluphenazine decanoate*, Flufenazin*, Fluphenazine Hydrochloride*, Lyogen*, Prolixin*, Haloperidol*, Haldol*, Levomepromazin*, Levomeprazin*, Levopromazine*, Tisercin*, Tizercine*, Tizertsin*, Methotrimeprazine*, Loxapine*, Loxapinsuccinate*, Oxilapine*, Cloxazepine*, Loxapine Monohydrochloride*, Loxipine Maleate*, Loxipine Succinate*, Loxitane*, Asendin*, Desmethylloxapine*, Amoxapine*, Olanzapine*, Perphenazine*, Chlorpiprazine*, Perfenazine*, Trilafonor*, Pimozide*, Prothipendyl*, Quetiapine*, Fumarate*, Risperidone*, Risperidal*, Sulpiride*, Dogmatil*, Eglonyl*, Sulperide*, Thioridazine*, Meleril*, Mellaril*, Melleril*, Melleryl*, Sonapax*, Thioridazine Hydrochloride*, Tiaprid*, Tiapridal*, Trifluoperazine Hydrochloride*, Trifluoroperazine*, Triftazin*, Stelazine*, Trifluperazine*, Tripfluoperazine Hydrochloride*, Cisordinol*, Zuclopenthixol*, Clopenthixol*
Thesaurus
Explode Neuroleptic-Drugs

B.Pain (combined with OR)
Free Term
pain*
Thesaurus
explode Pain

C.RCT-Filter (combined with OR)
placebo*
random*
control*
prospectiv*
volunteer*
(clin* near trial*)
(compar* near stud*)
(singl* or doubl* or trebl* or tripl*) near (blind* or mask*)
The Cochrane LIbrary(Controlled vocabulary terms (MeSH) are presented in uppercase text; freetext terms in lowercase text.)

1. ANTIPSYCHOTIC AGENTS
2. antipsychotic$
3. neuroleptic$
4. (amisulpride or chlormethiazole or (chlorpromazine next hydrochloride) or chlorprothixene or clozapine or dixyrazine or (flupenthixol next decanoate) or (fluphenazine next decanoate) or haloperidol or levomepromazine or loxapine or (melperone next hydrochloride) or methotrimeprazine or olanzapine or perphenazine or pimozide or (prothipendyl next hydrochloride) or (quetiapine next fumarate) or risperidone or sulpiride or thioridazine or (tiapride next hydrochloride) or (trifluoperazine next hydrochloride) or ziprasidone or zotepine or zuclopenthixol)
5. OR/1-4
6. PAIN (Explode term)
7. VASCULAR HEADACHES (Explode term)
8. PAIN MEASUREMENT
9. neuralgi$
10 pain$
11. migrain$
12. OR/6-11
13. 5 AND12

Appendix 3. Updated searches January 2013

MEDLINE (OVID) Oct 2011 to 11/01/13

1 Antipsychotic Agents/ (38296)

2 (antipsychotic* or neuroleptic*).tw. (36477)

3 (neurolept* or antipsychotic* or Amisulpride* or Chormethiazole* or Clomethiazole* or Distraneurin* or Chlorpromazin* or Aminazine* or Chlorazine* or Chlordelazine* or Contomin* or Fenactil* or Largactil* or Propaphenin* or Thorazine* or "Flupenthixol decanoate* or Emergil*" or Fluanxol* or Flupentixol* or alphaFlupenthixol* or cisFlupenthixol* or Fluphenazin* or "Fluphenazine decanoate*" or Flufenazin* or "Fluphenazine Hydrochloride*" or Lyogen* or Prolixin* or Haloperidol* or Haldol* or Levomepromazin* or Levomeprazin* or Levopromazine* or Tisercin* or Tizercine* or Tizertsin* or Methotrimeprazine* or Loxapine* or Loxapinsuccinate* or Oxilapine* or Cloxazepine* or "Loxapine Monohydrochloride*" or "Loxipine Maleate*" or "Loxipine Succinate*" or Loxitane* or Asendin* or Desmethylloxapine* or Amoxapine* or Olanzapine* or Perphenazine* or Chlorpiprazine* or Perfenazine* or Trilafonor* or Pimozide* or Prothipendyl* or Quetiapine* or Fumarate* or Risperidone* or Risperidal* or Sulpiride* or Dogmatil* or Eglonyl* or Sulperide* or Thioridazine* or Meleril* or Mellaril* or Melleril* or Melleryl* or Sonapax* or "Thioridazine Hydrochloride*" or Tiaprid* or Tiapridal* or "Trifluoperazine Hydrochloride*" or Trifluoroperazine* or Triftazin* or Stelazine* or "Trifluperazine*or Tripfluoperazine Hydrochloride*or Cisordinol*" or "Zuclopenthixol*or Clopenthixol*,or Clozapine*or Melperone hydrochloride*or Ziprasidone*or Zotemine*").mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier] (99220)

4 Pimozide/ (1648)

5 Perphenazine/ (1405)

6 exp Loxapine/ (547)

7 Methotrimeprazine/ (670)

8 Haloperidol/ (14331)

9 Fluphenazine/ (2275)

10 Flupenthixol/ (809)

11 Chlorpromazine/ (15304)

12 Chlormethiazole/ (751)

13 Clopenthixol/ (360)

14 Trifluoperazine/ (3342)

15 Tiapride Hydrochloride/ (0)

16 Thioridazine/ (2154)

17 Sulpiride/ (3544)

18 Risperidone/ (4655)

19 Fumarates/ (3100)

20 or/1-19 (102158)

21 exp Pain/ (282471)

22 pain*.tw. (378943)

23 or/21-22 (504903)

24 20 and 23 (1768)

25 randomized controlled trial.pt. (336937)

26 controlled clinical trial.pt. (84917)

27 randomized.ab. (240687)

28 placebo.ab. (134089)

29 drug therapy.fs. (1568585)

30 randomly.ab. (172962)

31 trial.ab. (247676)

32 groups.ab. (1131458)

33 25 or 26 or 27 or 28 or 29 or 30 or 31 or 32 (2921812)

34 exp animals/ not humans.sh. (3747051)

35 33 not 34 (2482012)

36 24 and 35 (1002)

37 (201110* or 201111* or 201112* or 2012*).ed. (946315)

38 36 and 37 (51)

CENTRAL (The Cochrane Library) Issue 12 of 12 (2012)

#1 MeSH descriptor: [Antipsychotic Agents] this term only

#2 (antipsychotic* or neuroleptic*)

#3 (neurolept* or antipsychotic* or Amisulpride* or Chormethiazole* or Clomethiazole* or Distraneurin* or Chlorpromazin* or Aminazine* or Chlorazine* or Chlordelazine* or Contomin* or Fenactil* or Largactil* or Propaphenin* or Thorazine* or Flupenthixol decanoate* or Emergil* or Fluanxol* or Flupentixol* or alphaFlupenthixol* or cisFlupenthixol* or Fluphenazin* or Fluphenazine decanoate* or Flufenazin* or Fluphenazine Hydrochloride* or Lyogen* or Prolixin* or Haloperidol* or Haldol* or Levomepromazin* or Levomeprazin* or Levopromazine* or Tisercin* or Tizercine* or Tizertsin* or Methotrimeprazine* or Loxapine* or Loxapinsuccinate* or Oxilapine* or Cloxazepine* or Loxapine Monohydrochloride* or Loxipine Maleate* or Loxipine Succinate* or Loxitane* or Asendin* or Desmethylloxapine* or Amoxapine* or Olanzapine* or Perphenazine* or Chlorpiprazine* or Perfenazine* or Trilafonor* or Pimozide* or Prothipendyl* or Quetiapine* or Fumarate* or Risperidone* or Risperidal* or Sulpiride* or Dogmatil* or Eglonyl* or Sulperide* or Thioridazine* or Meleril* or Mellaril* or Melleril* or Melleryl* or Sonapax* or Thioridazine Hydrochloride* or Tiaprid* or Tiapridal* or Trifluoperazine Hydrochloride* or Trifluoroperazine* or Triftazin* or Stelazine* or "Trifluperazine*or Tripfluoperazine Hydrochloride* or Cisordinol*" or Zuclopenthixol* or Clopenthixol* or Clozapine*or Melperone hydrochloride* or Ziprasidone* or Zotemine*)

#4 MeSH descriptor: [Pimozide] this term only

#5 MeSH descriptor: [Perphenazine] this term only

#6 MeSH descriptor: [Loxapine] explode all trees

#7 MeSH descriptor: [Methotrimeprazine] this term only

#8 MeSH descriptor: [Haloperidol] this term only

#9 MeSH descriptor: [Fluphenazine] this term only

#10 MeSH descriptor: [Flupenthixol] this term only

#11 MeSH descriptor: [Chlorpromazine] this term only

#12 MeSH descriptor: [Chlormethiazole] this term only

#13 MeSH descriptor: [Clopenthixol] this term only

#14 MeSH descriptor: [Trifluoperazine] this term only

#15 MeSH descriptor: [Thioridazine] this term only

#16 MeSH descriptor: [Sulpiride] this term only

#17 MeSH descriptor: [Risperidone] this term only

#18 MeSH descriptor: [Fumarates] this term only

#19 #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18

#20 MeSH descriptor: [Pain] explode all trees

#21 pain*

#22 #20 or #21

#23 #19 and #22 from 2011 to 2013

EMBASE (OVID) Oct 2011 to 2013 week 03

1 Antipsychotic Agents/ (58700)

2 (antipsychotic* or neuroleptic*).tw. (55785)

3 (neurolept* or antipsychotic* or Amisulpride* or Chormethiazole* or Clomethiazole* or Distraneurin* or Chlorpromazin* or Aminazine* or Chlorazine* or Chlordelazine* or Contomin* or Fenactil* or Largactil* or Propaphenin* or Thorazine* or "Flupenthixol decanoate* or Emergil*" or Fluanxol* or Flupentixol* or alphaFlupenthixol* or cisFlupenthixol* or Fluphenazin* or "Fluphenazine decanoate*" or Flufenazin* or "Fluphenazine Hydrochloride*" or Lyogen* or Prolixin* or Haloperidol* or Haldol* or Levomepromazin* or Levomeprazin* or Levopromazine* or Tisercin* or Tizercine* or Tizertsin* or Methotrimeprazine* or Loxapine* or Loxapinsuccinate* or Oxilapine* or Cloxazepine* or "Loxapine Monohydrochloride*" or "Loxipine Maleate*" or "Loxipine Succinate*" or Loxitane* or Asendin* or Desmethylloxapine* or Amoxapine* or Olanzapine* or Perphenazine* or Chlorpiprazine* or Perfenazine* or Trilafonor* or Pimozide* or Prothipendyl* or Quetiapine* or Fumarate* or Risperidone* or Risperidal* or Sulpiride* or Dogmatil* or Eglonyl* or Sulperide* or Thioridazine* or Meleril* or Mellaril* or Melleril* or Melleryl* or Sonapax* or "Thioridazine Hydrochloride*" or Tiaprid* or Tiapridal* or "Trifluoperazine Hydrochloride*" or Trifluoroperazine* or Triftazin* or Stelazine* or "Trifluperazine*or Tripfluoperazine Hydrochloride*or Cisordinol*" or "Zuclopenthixol*or Clopenthixol*,or Clozapine*or Melperone hydrochloride*or Ziprasidone*or Zotemine*").mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword] (194441)

4 Pimozide/ (7142)

5 Perphenazine/ (6563)

6 exp Loxapine/ (1943)

7 Methotrimeprazine/ (4973)

8 Haloperidol/ (49400)

9 Fluphenazine/ (8860)

10 Flupenthixol/ (4196)

11 Chlorpromazine/ (42097)

12 Chlormethiazole/ (2771)

13 Clopenthixol/ (767)

14 Trifluoperazine/ (9676)

15 Tiapride Hydrochloride/ (1713)

16 Thioridazine/ (11514)

17 Sulpiride/ (10861)

18 Risperidone/ (24372)

19 Fumarates/ (1849)

20 or/1-19 (199428)

21 exp Pain/ (727482)

22 pain*.tw. (554811)

23 or/21-22 (949124)

24 20 and 23 (13310)

25 random$.tw. (790580)

26 factorial$.tw. (20622)

27 crossover$.tw. (46266)

28 cross over$.tw. (21047)

29 cross-over$.tw. (21047)

30 placebo$.tw. (189432)

31 (doubl$ adj blind$).tw. (140094)

32 (singl$ adj blind$).tw. (13242)

33 assign$.tw. (219299)

34 allocat$.tw. (74370)

35 volunteer$.tw. (169764)

36 Crossover Procedure/ (36012)

37 double-blind procedure.tw. (224)

38 Randomized Controlled Trial/ (338179)

39 Single Blind Procedure/ (16894)

40 or/25-39 (1296258)

41 (animal/ or nonhuman/) not human/ (4558955)

42 40 not 41 (1142927)

43 24 and 42 (2327)

44 (201110* or 201111* or 201112* or 2012* or 2013*).dd. (1627558)

45 43 and 44 (276)

PsycINFO (OVID) 2011 to Jan week 3 2013

1 Neuroleptic Drugs/ (13626)

2 (antipsychotic* or neuroleptic*).tw. (24917)

3 (neurolept* or antipsychotic* or Amisulpride* or Chormethiazole* or Clomethiazole* or Distraneurin* or Chlorpromazin* or Aminazine* or Chlorazine* or Chlordelazine* or Contomin* or Fenactil* or Largactil* or Propaphenin* or Thorazine* or "Flupenthixol decanoate* or Emergil*" or Fluanxol* or Flupentixol* or alphaFlupenthixol* or cisFlupenthixol* or Fluphenazin* or "Fluphenazine decanoate*" or Flufenazin* or "Fluphenazine Hydrochloride*" or Lyogen* or Prolixin* or Haloperidol* or Haldol* or Levomepromazin* or Levomeprazin* or Levopromazine* or Tisercin* or Tizercine* or Tizertsin* or Methotrimeprazine* or Loxapine* or Loxapinsuccinate* or Oxilapine* or Cloxazepine* or "Loxapine Monohydrochloride*" or "Loxipine Maleate*" or "Loxipine Succinate*" or Loxitane* or Asendin* or Desmethylloxapine* or Amoxapine* or Olanzapine* or Perphenazine* or Chlorpiprazine* or Perfenazine* or Trilafonor* or Pimozide* or Prothipendyl* or Quetiapine* or Fumarate* or Risperidone* or Risperidal* or Sulpiride* or Dogmatil* or Eglonyl* or Sulperide* or Thioridazine* or Meleril* or Mellaril* or Melleril* or Melleryl* or Sonapax* or "Thioridazine Hydrochloride*" or Tiaprid* or Tiapridal* or "Trifluoperazine Hydrochloride*" or Trifluoroperazine* or Triftazin* or Stelazine* or "Trifluperazine*or Tripfluoperazine Hydrochloride*or Cisordinol*" or "Zuclopenthixol*or Clopenthixol*,or Clozapine*or Melperone hydrochloride*or Ziprasidone*or Zotemine*").mp. [mp=title, abstract, heading word, table of contents, key concepts, original title, tests & measures] (32805)

4 Pimozide/ (196)

5 Perphenazine/ (103)

6 exp Loxapine/ (45)

7 Haloperidol/ (3295)

8 Fluphenazine/ (257)

9 Chlorpromazine/ (363)

10 Trifluoperazine/ (44)

11 Thioridazine/ (145)

12 Sulpiride/ (370)

13 Risperidone/ (2980)

14 exp Pain/ (33805)

15 pain*.tw. (60478)

16 or/14-15 (67780)

17 or/1-13 (32819)

18 16 and 17 (485)

19 clinical trials/ (6454)

20 (randomis* or randomiz*).tw. (39468)

21 (random$ adj3 (allocat$ or assign$)).tw. (22565)

22 ((clinic$ or control$) adj trial$).tw. (33593)

23 ((singl$ or doubl$ or trebl$ or tripl$) adj3 (blind$ or mask$)).tw. (15295)

24 (crossover$ or "cross over$").tw. (5462)

25 random sampling/ (445)

26 Experiment Controls/ (435)

27 Placebo/ (2888)

28 placebo$.tw. (23824)

29 exp program evaluation/ (12478)

30 treatment effectiveness evaluation/ (11837)

31 ((effectiveness or evaluat$) adj3 (stud$ or research$)).tw. (45024)

32 or/19-31 (141635)

33 18 and 32 (82)

34 limit 33 to yr="2011 -Current" (17)

Feedback

Studies on prochlorperazine and droperidol, 31 October 2013

Summary

Feedback: The methods state that the update included two additional antipsychotics - prochlorperazine and droperidol that were excluded from the original review. This is in contrast with the results text where you state:

Three high-quality studies (Brousseau 2004; Richman 2002; Weaver 2004) were excluded because the antipsychotics tested (prochlorperazine and droperidol) had not been within the scope of antipsychotics of our protocol and because they were not within the scope of our search strategy.

It is unclear why these studies were not included in the update (even if left out of the original) if part of the purpose was to expand it to include these other drugs. Ultimately, two of the most commonly used antipsychotics in the US (including frequent use for acutely painful conditions) are left out of the review making much less clinically useful to practitioners.

Reply

We are grateful for this clinically relevant feedback and revised our review accordingly. To summarize, the reasons for exclusion of the studies have been corrected (see Brousseau 2004 and Weaver 2004). Another study (Richman 2002a) investigating the effect of droperidol on migraine headaches has now been included.

Contributors

Authors and editors.

What's new

DateEventDescription
27 November 2015Review declared as stableSee Published notes.

History

Protocol first published: Issue 3, 2004
Review first published: Issue 4, 2008

DateEventDescription
7 November 2013Feedback has been incorporatedInclusion of studies on prochlorperazine and droperidol. See Feedback 1.
4 September 2013AmendedSlight amendment to wording of search strategy.
21 August 2013New citation required but conclusions have not changedThis search found five new studies which were all excluded, so the review remains the same as previously.
7 February 2013New search has been performedThis review is an update of the original review published in The Cochrane Library in 2008. See Published notes.
9 November 2009AmendedContact details updated.

Contributions of authors

Stefan Seidel: final draft of the manuscript.
Thomas Sycha, Martin Aigner, Michael Ossege: search strategy and protocol, conceived and planned the review, quality assessment of identified studies, revision of the manuscript.
Elisabeth Pernicka: statistics.
Brigitte Wildner: search strategy, delivery of printed versions.

Declarations of interest

None known.

Sources of support

Internal sources

  • Department of Psychiatry, University of Vienna Medical School, Austria.

External sources

  • No sources of support supplied

Notes

This review was first published in Issue 4, 2008. Citation: Seidel S, Aigner M, Ossege M, Pernicka E, Wildner B, Sycha T. Antipsychotics for acute and chronic pain in adults. Cochrane Database of Systematic Reviews 2008, Issue 4. Art. No.: CD004844. DOI: 10.1002/14651858.CD004844.pub2.

At November 2015, the authors and editors have agreed to split this review into separate titles which will serve to update and replace the original. The planned titles are for antipsychotics for headache and migraine, and neuropathic pain. For more information, please contact the PaPaS CRG.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Bussone 1980

MethodsDouble-blind, placebo-controlled trial
Participants50 patients, 40 mixed headache, 10 classical migraine
Age range between 17 and 68 years
Interventions

Random assignment to either 300 mg tiapride or placebo

Duration of treatment: not stated

OutcomesHeadache intensity, frequency and duration reported by headache diary (including 4 weeks pre-intervention)
NotesType of pain: chronic headache; 1 dropout due to nausea in the treatment group
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot reported
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot reported
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll participants were included in the analysis, no withdrawals
SizeHigh riskFewer than 50 participants/treatment arm

Davidsen 1979

MethodsDouble-blind, controlled, randomised trial
Participants

316 patients, mean age: levomepromazine group 67 years, pethidine group 68 years. Inclusion criteria: acute myocardial infarction within 24 hours prior to admission
Exclusion criteria: known adverse reactions to narcotics or phenothiazines, treatment with levomepromazine before admission.

Comorbidities: previous hypertension (32 (17% versus 21 (15%)) and previous heart insufficiency (73 (39%) versus 63 (44%)) in the levomepromazine and pethidine groups

Interventions

Patients received one injection upon admission (50 mg pethidine or 12.5 mg levomepromazine) and 100 mg pethidine or 25 mg levomepromazine orally 3 times a day for 3 consecutive days

Further injections were given when needed

Outcomes

Pain intensity was assessed every 30 minutes during the first 6 hours after admission

90% of patients encountered pain during the course of the acute myocardial infarction

Recurrences of pain in the first 72 hours were observed in 50% of the levomepromazine-treated and in 62% of the pethidine-treated patients (P<0.05)

Incidence of nausea was significantly higher in the pethidine-treated group (P<0.001)

Until a one-year follow-up mortality rates were significantly lower in the levomepromazine-treated group

NotesType of pain: pain in myocardial infarction; 3 patients died within 30 min after admission, 5 were not treated according to the protocol.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported - stated to be "on admission the patient was allocated the first available box"
Allocation concealment (selection bias)Unclear riskNot reported
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDescribed as "tablets and vials of identical appearance were dispensed ..." and "...the sealed code was kept in the pharmacy ..."
Blinding of outcome assessment (detection bias)
All outcomes
Low riskDescribed as "tablets and vials of identical appearance were dispensed ..." and "...the sealed code was kept in the pharmacy ..."
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll participants were included in the analysis, no withdrawals
SizeLow risk>100 participants/treatment arm

Ginsberg 1983

MethodsDouble-blind, randomised trial
Participants

42 patients, 16 male, 26 female. Inclusion criteria: definite soft tissue rheumatism, sole location of pain, continuous pain, pain of non-specific origin
Exclusion criteria: not stated

None had received analgesics for the current affection before entering the study

InterventionsRandomly assigned to 100 mg tiapride or 200 mg glafenine 3 times daily over a period of 14 days
Outcomes

Pain intensity (VAS) was assessed once daily

Initial VAS score: 73 mm (tiapride group) and 73 mm (glafenine group)
VAS score on day 14: 18.4 mm (tiapride group) and 30.4 mm (glafenine group)

Mild side effects in tiapride group (6 drowsiness, 2 gastric intolerance)

No interruption of treatment
By the end of treatment, pain had disappeared in 76% of tiapride-treated and 43% of the glafenine-treated patients

NotesType of pain: acute rheumatic pain; no differences between sexes regarding the efficacy rating of the drugs.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot reported
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot reported
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll participants were included in the analysis, no withdrawals
SizeHigh riskFewer than 50 participants/treatment arm

Graff-Radford 2000

MethodsDouble-blind, placebo-controlled, randomised trial
Participants49 patients, mean age 72.9 years
Inclusion criteria: post-herpetic neuralgia, pain duration equal or longer to 6 months
Exclusion criteria: not stated
Interventions

Random assignment to 4 groups:
Group 1: amitriptyline
Group 2: amitriptyline + fluphenazine
Group 3: fluphenazine
Group 4: placebo (active to mimic anticholinergic side effects)

Starting dose 12.5 mg (amitriptyline) and 1 mg (fluphenazine)
Maximum dose 200 mg (amitriptyline) and 3 mg (fluphenazine)

8 weeks, one visit per week

Outcomes

Visual analogue scale (VAS), McGill Pain questionnaire (MPQ), side effects scale, Minnesota Multiphasic Personality Inventory (MMPI), Beck Depression Inventory (BDI), Spielberger State Trait Anxiety Inventory (SSTAI)

VAS: significant changes in Group 1 and 2, but none in Group 3 or 4
Side effects: highest level in Group 3

No evident changes in psychometric measurements

NotesType of pain: post-herpetic neuralgia; 1 dropout due to heavy sedation effect due to amitriptyline.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot described - states “randomly assigned”
Allocation concealment (selection bias)Unclear riskNot reported
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-dummy method. “Active” placebo (glycopyrrolate) to mimic anticholinergic side effects
Blinding of outcome assessment (detection bias)
All outcomes
Low riskDouble-dummy method. “Active” placebo (glycopyrrolate) to mimic anticholinergic side effects
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskImputation method not described
SizeHigh riskFewer than 50 participants/treatment arm

Honkaniemi 2006

MethodsDouble-blind, placebo-controlled, randomised trial
Participants47 patients, 41 female, 6 male, mean age 36 years, mean duration of headache before admission 75 hours. Inclusion criteria: diagnosis of migraine according to the IHSCC. Exclusion criteria: long QT-interval, usage of drugs prolonging QT-interval, hepatic disease, epilepsy or history of seizures, hyperthyreosis, parkinsonism, chronic psychiatric disease, other neuroleptic medication, and intoxication
InterventionsRandom assignment to either 5 mg haloperidol in 500 ml of normal saline or 500 ml of normal saline alone as a 20 to 30 minute infusion
OutcomesPain estimation by a VAS between 1 hour and 3 hours after the infusion
Marked or almost total pain relief
NotesType of pain: acute migraine headache; 44 patients included in the placebo-controlled arm of the trial. Of these, 4 were rejected: 2 were included in the study twice, 1 did not fulfil the inclusion criteria and 1 was pain free before the infusion. Of the remaining 40, 36 were female and 4 male. The mean duration of the headache for these 40 patients was 67 h. 80% of patients reported side effects, mainly motor agitation (53%) and sedation (53%).
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskDescribed as "...patients were randomized by envelope selection."
Allocation concealment (selection bias)Unclear riskNot reported
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDescribed as "...treatment was carried out by an attending nurse, who prepared and blinded the infusion."
Blinding of outcome assessment (detection bias)
All outcomes
Low riskDescribed as "...treatment was carried out by an attending nurse, who prepared and blinded the infusion."
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskImputation method not described
SizeHigh riskFewer than 50 participants/treatment arm

Johnston 1972

MethodsRandomised, double-blind, placebo-controlled trial
Participants50 patients, 32 outpatients, 18 inpatients, 6 men, 44 women, mean age 56 years (age range between 31 to 73 years). Inclusion criteria: terminal cancer with a prognosis of a least a 6 week survival
Exclusion criteria: not stated
InterventionsRandom assignment to either 25 mg thioridazine p.o. or placebo 3 times a day (final dose 75 mg) for 3 weeks
Outcomes

Physician's weekly rating of anxiety-tension, insomnia, crying spells, fears, anorexia, and withdrawal, overall rating of emotional complaints and pain

Statistically significant changes in the thioridazine group for anxiety-tension, depressive mood, restlessness, insomnia, crying spells, fears, overall rating of emotional complaints and pain compared to placebo

NotesType of pain: cancer pain; 3 dropouts during follow-up. No untoward effects were observed.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDescribed as "matching placebo capsules"
Blinding of outcome assessment (detection bias)
All outcomes
Low riskDescribed as "matching placebo capsules"
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskImputation method not described
SizeHigh riskFewer than 50 patients/treatment arm

Judkins 1982

MethodsRandomised, double-blind, placebo-controlled trial
Participants34 patients, 18 to 70 years, both female and male
Inclusion criteria: scheduled for elective major upper abdominal surgery, otherwise fit
InterventionsPremedication of either 5 mg, 10 mg haloperidol or placebo
Outcomes

Analgesic requirement (on-demand system) as measured on a visual analogue scale was assessed every 3 hours within the first 24 hours following surgery

No significant differences between all three conditions regarding the analgesic requirements

Postoperative emesis reduced in the groups receiving haloperidol

NotesType of pain: postoperative pain.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot reported
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot reported
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll participants were included in the analysis, no withdrawals
SizeHigh riskFewer than 50 patients/treatment arm

Langemark 1994

MethodsRandomised, double-blind, cross-over, response-conditional pilot study
Participants50 patients, mean age 42 years, recruited by mailed questionnaire
Inclusion criteria: chronic tension-type headache for at least 6 months and no more than 14 headache-free days per month
InterventionsRandom assignment to either 20 mg paroxetine or 400 mg sulpiride (starting with 200 mg for 1 week) daily for 8 weeks
Outcomes

Headache diary beginning 4 weeks prior to treatment and during 8 weeks of treatment (5-point verbal scale (no/slight/moderate/very troublesome/worst possible headache)

Change in headache score: drug given first, paroxetine (n=18) -0.4, sulpiride (n=19) -0.7

Notes

Type of pain: chronic tension-type headache; 8 patients dropped out during treatment, 3 headache diaries were incomplete.

1 patient offered paroxetine first never took the drug.

Depression was ruled out using the Bech-Rafaelsen Melancholia rating scale.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-dummy technique described as "identically looking placebo tablets"
Blinding of outcome assessment (detection bias)
All outcomes
Low riskDouble-dummy technique described as "identically looking placebo tablets"
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskImputation method not described
SizeHigh riskFewer than 50 patients/treatment arm

Lechin 1989

MethodsDouble-blind placebo-controlled cross-over trial
Four-centre study
Participants68 patients joined the study, final number 48 outpatients, 24 men and 24 women, duration of illness 8 to 17 years
Inclusion criteria: severe facial pain for at least 2 years, clinical diagnosis of trigeminal neuralgia
Exclusion criteria: placebo responder (improvement of more than 20% during placebo washout period), severe physical illness, history of psychotic episodes, alcohol or drug addiction, epilepsy or any other convulsive disorder
Interventions4 weeks of placebo washout, 8 weeks of treatment following random assignment to carbamazepine (final dose of 1200 mg with a 14-day titration period) or pimozide (final dose of 12 mg with a 14-day titration period), 4 weeks with abrupt withdrawal and placebo substitution, 8 weeks of cross-over treatment
Outcomes

Pain intensity using 6-point registration cards (0 = no pain, 6 = pain present, cannot be ignored, prompt medical advice sought), duration, frequency, basal pain, sensitivity of trigger zones, number of relief tablets

Total trigeminal neuralgia score reduction of 78.1 % (pimozide group) compared to 49.7% (carbamazepine group), statistically significant (P<0.001) at week 10

Adverse effects (hand tremors, involuntary movements during sleep, slight Parkinson's symptoms) observed in 40 of 48 patients

Notes

Type of pain: trigeminal neuralgia; 9 patients were not admitted to the treatment phase, 6 patients were excluded.

11 were not included in the statistical analysis.

All patients refused interruption of pimozide treatment.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskDescribed as "identical dark capsules"
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskDescribed as "identical dark capsules"
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskImputation method not described
SizeHigh riskFewer than 50 patients/treatment arm

Richman 2002

MethodsDouble-blind single-center randomized controlled trial
Participants

Twenty-nine patients admitted to emergency department due to acute headaches

Inclusion criteria: migraine with or without aura according the criteria of the International Headache Society
Exclusion criteria: refusal to give informed consent, known allergy to butyrophenones and/or narcotics, ingestion of antiemetic, antihistamine, phenothiazine, and/or narcotic medication within 24 hours of ED presentation, diagnostic work-up because headache was not typical in character compared with the patient's prior migraine pattern

Interventions2.5mg intramuscular droperidol (group 1) and 1.5mg/kg intramuscluar meperidine
Outcomespain intensity (VAS) after 30 minutes
Notesnone
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskonly patients with acute migraine, presumably those with higher pain intensity due to presentation in ED
Allocation concealment (selection bias)Unclear riskNot described
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot described
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot described
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskImputation method not described
SizeHigh riskVery small group size

Roux 1983

MethodsDouble-blind, placebo-controlled, randomised trial
Participants30 patients
Headache following rachiocentesis (observation period 48 hours)
Inclusion criteria: not stated
Exclusion criteria: not stated
InterventionsRandom assignment to either 200 mg tiapride i.v. or placebo i.v. after rachiocentesis
Outcomes

Occurrence of headache

No headache in 86.7% of patients receiving tiapride and in 46.6% of patients receiving placebo

Statistically significant difference

NotesType of pain: post-rachiocentesis headache.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot reported
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot reported
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskImputation method not described
SizeHigh riskFewer than 50 patients/treatment arm

Zitman 1991

  1. a

    i.v. - intravenous

MethodsDouble-blind, placebo-controlled cross-over trial study
Participants34 patients, mean age 34 years
Inclusion criteria: pain duration at least 6 months, age between 30 and 60 years
Exclusion criteria: severe psychiatric disease, renal, hepatic or cardiac disorders, epilepsy, glaucoma, hypertension, prostate dysfunction
InterventionsBaseline (2 weeks) 75 mg amitriptyline and 3 mg flupentixol; first treatment (5 weeks) 75 mg amitriptyline and 3 mg flupentixol (scheme A) or 75 mg amitriptyline alone (scheme B); washout period (2 weeks) both groups placebo; 2nd treatment (5 weeks) crossing-over from scheme A to B and vice versa
Outcomes

Zung depression scale, Hamilton depression scale, clinical screening for extrapyramidal side effects, Abnormal Involuntary Movement Scale (AIMS), pain intensities (numeric scale 0 = no pain, 10 = unbearable pain)

No differences between the amitriptyline group and the amitriptyline + flupentixol group concerning the pain

NotesType of pain: somatoform pain disorder; 2 refused to participate, 9 dropped out during treatment
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDescribed as "identical placebo tablets"
Blinding of outcome assessment (detection bias)
All outcomes
Low riskDescribed as "identical placebo tablets"
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskImputation method not described
SizeHigh riskFewer than 50 patients/treatment arm

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Adeloye 1971no data
Anon 1986not able to identify authors
Barbier 1989haloperidol in combination with buzepide metiodide
Brousseau 2004pediatric population studied
Cerbo 1982across-over trial, no data on first session given separately
Cerbo 1982bcross-over trial
Clavel 1980cross-over trial
Clavel 1984cross-over trial
Corazza 1996mixed outcome
no distinct outcome pain parameter, overall score
Friedman 2008control group: metoclopramide
Girard 1970open-label study, no control condition, no randomisation
Gomez-Perez 1985fluphenazine in combination with nortriptyline
Gomez-Perez 1996cross-over design
Grillage 1986control group: diazepam
Hakkarainen 1973cross-over
Hakkarainen 1977no randomisation
Hill 2008control group: droperidol
Jokinen 1984control group: diazepam
Kostic 2010combination
Lam 1978pain no outcome
Lancaster-Smith 1982combination
Le Derff 1982open-label study
Lobera 1980mix outcome (pain/nausea/emesis)
Macarri 1992control group: antipsychotic
Maina 2002single blind
Martin 1984fluphenazine in combination with nortriptyline
no pain outcome
Menault 1981no randomization, no placebo control
Mendel 1986combination of amitriptyline and fluphenazine
Mereto 1974in all three groups perphenazine
Miller 2009control group: octreotide
Pagliarini 1968single blind
Pisani 1984no blinding
Potvin 2012pain no primary outcome
Predescu 1973no pain outcome
Rennemo 1982pain no primary outcome
not compared to placebo or other compound in respect to pain
Steinbrook 1998postoperative pain was treated as needed with fentanyl or morphine
no pain outcome
Van Kempen 1992pain no outcome
Weaver 2004comparison of two antipsychotics without placebo
Weber 1980additional pain medication
Wohlzogen 1970healthy subjects
Zitman 1992no randomisation

Ancillary