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Antipsychotics for acute and chronic pain in adults

  1. Stefan Seidel1,*,
  2. Martin Aigner2,
  3. Michael Ossege2,
  4. Elisabeth Pernicka3,
  5. Brigitte Wildner4,
  6. Thomas Sycha1

Editorial Group: Cochrane Pain, Palliative and Supportive Care Group

Published Online: 29 AUG 2013

Assessed as up-to-date: 21 AUG 2013

DOI: 10.1002/14651858.CD004844.pub3


How to Cite

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 2013, Issue 8. Art. No.: CD004844. DOI: 10.1002/14651858.CD004844.pub3.

Author Information

  1. 1

    Medical University of Vienna, Department of Neurology, Vienna, Austria

  2. 2

    Medical University of Vienna, Department of Psychiatry, Vienna, Austria

  3. 3

    Medical University of Vienna, Department of Medical Statistics, Vienna, Austria

  4. 4

    University Library of the Medical University of Vienna, Information Retrieval Office, Vienna, Austria

*Stefan Seidel, Department of Neurology, Medical University of Vienna, Währinger Straße 13a, Vienna, Austria. stefan.seidel@meduniwien.ac.at.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 29 AUG 2013

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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


InterventionsRandom 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


Participants316 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


InterventionsPatients 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


OutcomesPain 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


Participants42 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


OutcomesPain 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


InterventionsRandom 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


OutcomesVisual 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


OutcomesPhysician'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


OutcomesAnalgesic 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


OutcomesHeadache 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


NotesType 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


OutcomesPain 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


NotesType 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

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


OutcomesOccurrence 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

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


OutcomesZung 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 2004studied compound (that is prochlorperazine) not within scope of this review

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

Richman 2002studied compound (that is droperidol) not within scope of this review

Steinbrook 1998postoperative pain was treated as needed with fentanyl or morphine
no pain outcome

Van Kempen 1992pain no outcome

Weaver 2004studied compound (that is droperidol) not within scope of this review

Weber 1980additional pain medication

Wohlzogen 1970healthy subjects

Zitman 1992no randomisation

 
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 acute
140Mean Difference (IV, Fixed, 95% CI)-4.52 [-5.88, -3.16]

    1.2 chronic
3108Mean 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 acute
282Risk Ratio (M-H, Fixed, 95% CI)0.43 [0.25, 0.73]

 3 Acute and chronic pain continuous data - mean after treatment4Mean Difference (IV, Fixed, 95% CI)Totals not selected

    3.1 acute
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    3.2 chronic
3Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 
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%