Imipramine for neuropathic pain and fibromyalgia in adults

  • Protocol
  • Intervention

Authors


Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

  1. To assess the analgesic efficacy of imipramine for chronic neuropathic pain and fibromyalgia in adults.

  2. To assess the adverse events associated with the clinical use of imipramine for chronic neuropathic pain and fibromyalgia.

Background

This protocol is based on a template for reviews of drugs used to relieve neuropathic pain and fibromyalgia. Imipramine is a tricyclic antidepressant that is sometimes used to treat chronic neuropathic pain (pain due to nerve damage or changes in the central nervous system (CNS)) and fibromyalgia. Its use is recommended in some guidelines though this is an unlicensed indication.

Description of the condition

The 2011 International Association of the Study of Pain definition of neuropathic pain is "pain caused by a lesion or disease of the somatosensory system" (Jensen 2011) based on an earlier consensus meeting (Treede 2008). Neuropathic pain may be caused by nerve damage, but is often followed by changes in the central nervous system (CNS) (Moisset 2007). It is complex (Apkarian 2011; Tracey 2011), and neuropathic pain features can be found in patients with joint pain (Soni 2013).

Fibromyalgia is defined as widespread pain for longer than three months with pain on palpation at 11 or more of 18 specified tender points (Wolfe 1990), and is frequently associated with other symptoms such as poor sleep, fatigue, and depression. More recently, a definition of fibromyalgia has been proposed based on symptom severity and the presence of widespread pain (Wolfe 2010). The cause, or causes, are not well understood, but it has features in common with neuropathic pain, including changes in the CNS. Moreover, neuropathic pain and fibromyalgia patients experience similar sensory phenomena (Koroschetz 2011). Many people with these conditions are significantly disabled by moderate or severe pain for many years.

In primary care in the UK the incidences, per 100,000 person years observation, have been reported as 28 (95% CI 27 to 30) for postherpetic neuralgia, 27 (95% CI 26 to 29) for trigeminal neuralgia, 0.8 (95% CI 0.6 to 1.1) for phantom limb pain, and 21 (95% CI 20 to 22) for painful diabetic neuropathy (Hall 2008). Estimates vary between studies, often because of small numbers of cases. The incidence of trigeminal neuralgia has been estimated at 4 in 100,000 per year (Katusic 1991; Rappaport 1994), while more recently, a study of facial pain in The Netherlands found incidences per 100,000 person years of 12.6 for trigeminal neuralgia and 3.9 for postherpetic neuralgia (Koopman 2009). A systematic review of chronic pain demonstrated that some neuropathic pain conditions, such as painful diabetic neuropathy, can be more common, with prevalence rates up to 400 per 100,000 person years (McQuay 2007) illustrating how common the condition was as well as its chronicity. The prevalence of neuropathic pain was reported as being 3.3% in Austria (Gustorff 2008), 6.9% in France (Bouhassira 2008), as high as 8% in the UK (Torrance 2006), and about 7% in a systematic review of studies published since 2000 (Moore 2013a). Some forms of neuropathic pain, such as diabetic neuropathy and post surgical chronic pain (which is often neuropathic in origin), are increasing (Hall 2008). Fibromyalgia is common, especially in women, with an all-age prevalence of 12%, and a female to male ratio of 6:1 (McNally 2006).

Neuropathic pain and fibromyalgia are known to be difficult to treat effectively, with only a minority of individuals experiencing a clinically relevant benefit from any one intervention. A multidisciplinary approach is now advocated, with pharmacological interventions being combined with physical or cognitive interventions, or both. Conventional analgesics are usually not effective. Some patients may derive some benefit from a topical lidocaine patch or low concentration topical capsaicin, though evidence about benefits is uncertain (Derry 2012; Khaliq 2007). High concentration topical lidocaine may benefit some patients with postherpetic neuralgia (Derry 2013). Treatment is more usually by so-called unconventional analgesics such as antidepressants like duloxetine and amitriptyline (Lunn 2009; Moore 2012a; Sultan 2008) or antiepileptics like gabapentin or pregabalin (Moore 2009a; Moore 2011). An overview of treatment guidelines points out some general similarities, but also differences in approach (O'Connor 2009). The proportion of patients who achieve worthwhile pain relief (typically at least 50% pain intensity reduction (Moore 2013b)) is small, generally 10% to 25% more than with placebo, with the number needed to treat for an additional beneficial outcome (NNT) usually between 4 and 10.

Chronic painful conditions comprise five of the 11 top-ranking conditions for years lived with disability in 2010 (Vos 2012), and are responsible for considerable loss of quality of life, employment, and increased health costs (Moore 2013a).

Description of the intervention

Imipramine is a tricyclic antidepressant (TCA), most commonly used to treat depressive illness and nocturnal enuresis in children. It is partially converted in the body to an active metabolite, desipramine, another TCA. Imipramine is not licensed in the UK for treating neuropathic pain or fibromyalgia but is commonly used for these conditions. It is also used around the world for neuropathic pain, irrespective of licensing.

Imipramine is available as tablets (10 mg and 25 mg). For treating neuropathic pain, typical starting dosages are between 10 mg and 25 mg daily, usually taken at night, increasing to 75 mg daily if necessary. The main adverse effects are due to its anticholinergic activity and include dry mouth, weight gain and drowsiness (although it is less sedating than amitriptyline).

How the intervention might work

The mechanism of action of imipramine in the treatment of neuropathic pain and fibromyalgia remains uncertain, though it is known to be a strong reuptake inhibitor of serotonin and, to a lesser extent, norepinephrine (Watson 2013). Its active metabolite, desipramine, is conversely a very strong reuptake inhibitor of norepinephrine, and to a lesser extent, serotonin. The mechanism is likely to differ from that in depression since analgesia with TCAs is often achieved at lower doses than are needed for antidepressant effects. An alternative mechanism is likely to involve its action (as with many other analgesics) in blocking sodium channels in nerve membranes.

Why it is important to do this review

The earlier review of antidepressants for neuropathic pain (Saarto 2007) is being updated with separate reviews for individual drugs due to the large amount of data now available. These separate reviews will use more stringent criteria of validity, which include the level of response obtained, the duration of study and method of imputation of missing data (Moore 2012b). The individual reviews will be included in an overview of antidepressant drugs for neuropathic pain and fibromyalgia. Appendix 1 gives details of recent changes to the thinking about chronic pain and evidence.

This Cochrane review will assess evidence in ways that make both statistical and clinical sense, and will use developing criteria for what constitutes reliable evidence in chronic pain (Moore 2010a). Trials included and analysed will need to meet a minimum of reporting quality (blinding, randomisation), validity (duration, dose and timing, diagnosis, outcomes, etc) and size (ideally at least 500 participants in a comparison in which the NNT is four or above (Moore 1998)). This sets high standards and marks a departure from how reviews have been done previously.

Objectives

  1. To assess the analgesic efficacy of imipramine for chronic neuropathic pain and fibromyalgia in adults.

  2. To assess the adverse events associated with the clinical use of imipramine for chronic neuropathic pain and fibromyalgia.

Methods

Criteria for considering studies for this review

Types of studies

We will include studies if they are randomised controlled trials (RCTs) with at least 10 participants per treatment group and double-blind assessment of participant outcomes following two weeks of treatment or longer, although the emphasis of the review will be on studies of eight weeks or longer. We require full journal publication, with the exception of online clinical trial results summaries of otherwise unpublished clinical trials and abstracts with sufficient data for analysis. We will not include short abstracts (usually meeting reports). We will exclude studies that are non-randomised, studies of experimental pain, case reports and clinical observations.

Types of participants

Studies should include adult participants aged 18 years and above. Participants may have one or more of a wide range of chronic neuropathic pain conditions including (but not limited to):

  • painful diabetic neuropathy;

  • postherpetic neuralgia;

  • trigeminal neuralgia;

  • phantom limb pain;

  • postoperative or traumatic neuropathic pain;

  • complex regional pain syndrome;

  • cancer-related neuropathy;

  • human immunodeficiency virus (HIV) neuropathy;

  • spinal cord injury;

and

  • fibromyalgia;

  • complex regional pain syndrome (CRPS) Type I.

We will include studies of participants with more than one type of neuropathic pain; in such cases we will analyse results according to the primary condition. Migraine and headache studies will be excluded as they are the subject of another Cochrane review (Chronicle 2004).

Types of interventions

Oral imipramine, at any dose, administered for the relief of neuropathic pain or fibromyalgia and compared to placebo or any active comparator.

Types of outcome measures

We anticipate that studies will use a variety of outcome measures, with the majority of studies using standard subjective scales (numerical rating scale (NRS) or visual analogue scale (VAS)) for pain intensity or pain relief, or both. We are particularly interested in Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) definitions for moderate and substantial benefit in chronic pain studies (Dworkin 2008). These are defined as at least 30% pain relief over baseline (moderate), at least 50% pain relief over baseline (substantial), much or very much improved on Patient Global Impression of Change (PGIC) (moderate), and very much improved on PGIC (substantial). These outcomes concentrate on dichotomous outcomes where pain responses do not follow a normal (Gaussian) distribution. People with chronic pain desire high levels of pain relief, ideally more than 50%, and with pain not worse than mild (O'Brien 2010).

We will include a 'Summary of findings' table as set out in the author guide (AUREF 2012). The 'Summary of findings' table will include outcomes of at least 50% and at least 30% pain intensity reduction, PGIC, adverse event withdrawals, serious adverse events and death.

Primary outcomes
  1. Patient-reported pain relief of 30% or greater.

  2. Patient-reported pain relief of 50% or greater.

  3. PGIC much or very much improved.

  4. PGIC very much improved.

Secondary outcomes
  1. Any pain-related outcome indicating some improvement.

  2. Withdrawals due to lack of efficacy.

  3. Participants experiencing any adverse event.

  4. Participants experiencing any serious adverse event. Serious adverse events typically include any untoward medical occurrence or effect that at any dose results in death, is life-threatening, requires hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, is a congenital anomaly or birth defect, is an ‘important medical event’ that may jeopardise the patient, or may require an intervention to prevent one of the above characteristics/consequences.

  5. Withdrawals due to adverse events.

  6. Specific adverse events, particularly somnolence, dizziness, and weight gain.

These outcomes are not eligibility criteria for this review, but are outcomes of interest within whichever studies are included.

Search methods for identification of studies

Electronic searches

We will search the following databases:

  • Cochrane Central Register of Controlled Trials (CENTRAL);

  • MEDLINE (via Ovid);

  • EMBASE (via Ovid).

The search strategy for MEDLINE is in Appendix 2. There will be no language restrictions.

Searching other resources

We will search two clinical trials databases (ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (apps.who.int/trialsearch/)), together with the reference lists of included studies and relevant review articles. We do not plan to contact investigators or study sponsors.

Data collection and analysis

The intention is to perform separate analyses according to particular neuropathic pain conditions, or fibromyalgia. Analyses combining different neuropathic pain conditions will be done for exploratory purposes only.

Selection of studies

We will determine eligibility by reading the title and abstract of each study identified by the search. We will eliminate studies that clearly do not satisfy inclusion criteria, and we will obtain full copies of the remaining studies; decisions will be made by two review authors. Two review authors will read these studies independently and reach agreement by discussion. We will not anonymise the studies in any way before assessment. We will create a PRISMA flow chart if appropriate.

Data extraction and management

Two review authors will independently extract data using a standard form and check for agreement before entry into RevMan (RevMan 2012) or any other analysis tool. We will include information about the pain condition and number of participants treated, drug and dosing regimen, study design (placebo or active control), study duration and follow-up, analgesic outcome measures and results, withdrawals and adverse events (participants experiencing any adverse event, or serious adverse event).

Assessment of risk of bias in included studies

We will use the Oxford Quality Score (Jadad 1996) as the basis for inclusion, limiting inclusion to studies that are, as a minimum, randomised and double-blind.

Two authors will independently assess risk of bias for each study, using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) and adapted from those used by the Cochrane Pregnancy and Childbirth Group, with any disagreements resolved by discussion.

  1. We will assess the following for each study: Random sequence generation (checking for possible selection bias). We will assess the method used to generate the allocation sequence as: low risk of bias (any truly random process, for example random number table; computer random number generator); unclear risk of bias (method used to generate sequence not clearly stated). We will exclude studies using a non-random process (for example, odd or even date of birth; hospital or clinic record number).

  2. Allocation concealment (checking for possible selection bias). The method used to conceal allocation to interventions prior to assignment determines whether intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment. We will assess the methods as: low risk of bias (for example, telephone or central randomisation; consecutively numbered sealed opaque envelopes); unclear risk of bias (method not clearly stated). We will exclude studies that do not conceal allocation (for example, open list).

  3. Blinding of outcome assessment (checking for possible detection bias). We will assess the methods used to blind study participants and outcome assessors from knowledge of which intervention a participant received. We will assess the methods as: low risk of bias (study states that it was blinded and describes the method used to achieve blinding, for example, identical tablets; matched in appearance and smell); unclear risk of bias (study states that it was blinded but does not provide an adequate description of how it was achieved). We will exclude studies that were not double-blind.

  4. Incomplete outcome data (checking for possible attrition bias due to the amount, nature and handling of incomplete outcome data). We will assess the methods used to deal with incomplete data as: low risk (< 10% of participants did not complete the study and/or used ‘baseline observation carried forward’ analysis); unclear risk of bias (used 'last observation carried forward' analysis); high risk of bias (used 'completer' analysis).

  5. Size of study (checking for possible biases confounded by small size). We will assess studies as being at low risk of bias (≥ 200 participants per treatment arm); unclear risk of bias (50 to 199 participants per treatment arm); high risk of bias (< 50 participants per treatment arm).

Measures of treatment effect

We will calculate NNTs as the reciprocal of the absolute risk reduction (ARR) (McQuay 1998). For unwanted effects, the NNT becomes the number needed to treat for an additional harmful outcome (NNH) and is calculated in the same manner. We will use dichotomous data to calculate risk ratio (RR) with 95% confidence intervals (CI) using a fixed-effect model unless significant statistical heterogeneity is found (see below). Continuous data will not be used in analyses.

Unit of analysis issues

The control treatment arm would be split between active treatment arms in a single study if the active treatment arms were not combined for analysis.

If cross-over studies are identified for inclusion, we will use the first period only, if this is available. Where data for both periods are combined we will treat the study as if it was a parallel study, draw attention to the potential bias that this confers, and interpret the results accordingly.

Dealing with missing data

We will use intention-to-treat (ITT) analysis where the ITT population consists of participants who were randomised, took at least one dose of the assigned study medication, and provided at least one post-baseline assessment. Missing participants will be assigned zero improvement.

Assessment of heterogeneity

We will deal with clinical heterogeneity by combining studies that examine similar conditions. We will assess statistical heterogeneity visually (L'Abbé 1987) and with the use of the I² statistic. When I² is greater than 50%, we will consider possible reasons.

Assessment of reporting biases

The aim of this review is to use dichotomous data of known utility (Moore 2010c). The review does not depend on what authors of the original studies chose to report or not, though clearly difficulties will arise in studies failing to report any dichotomous results. We will extract and use continuous data, which probably poorly reflect efficacy and utility, if useful for illustrative purposes only.

We will assess publication bias using a method designed to detect the amount of unpublished data with a null effect required to make any result clinically irrelevant (usually taken to mean an NNT of 10 or higher) (Moore 2008).

Data synthesis

We plan to use a fixed-effect model for meta-analysis. We will use a random-effects model for meta-analysis if there is significant clinical heterogeneity and it is considered appropriate to combine studies.

We plan to analyse data for each painful condition in two tiers, according to outcome and freedom from known sources of bias.

  • The first tier will use data meeting current best standards, where studies report the outcome of at least 50% pain intensity reduction over baseline (or its equivalent), without the use of last observation carried forward (LOCF) or other imputation method for dropouts, report an ITT analysis, last 8 to 12 weeks or longer, have a parallel-group design, and where there are at least 200 participants (preferably at least 400) in the comparison. These top-tier results will be reported first.

  • The second tier will use any available data, but where one or more of these conditions are not met, for example reporting at least 30% pain intensity reduction, using LOCF or a completer analysis, lasting 4 to 8 weeks, and where the numbers of participants and studies are small.

Subgroup analysis and investigation of heterogeneity

We plan all analyses to be according to individual painful conditions, because placebo response rates with the same outcome can vary between conditions, as can the drug-specific effects (Moore 2009a).

Sensitivity analysis

We plan no sensitivity analysis because the evidence base is known to be too small to allow reliable analysis. We will examine details of dose escalation schedules in the unlikely situation that this could provide some basis for a sensitivity analysis.

Acknowledgements

Institutional support is provided by the Oxford Pain Relief Trust.

Appendices

Appendix 1. Methodological considerations for chronic pain

There have been several recent changes in how efficacy of conventional and unconventional treatments is assessed in chronic painful conditions. The outcomes are now better defined, particularly with new criteria of what constitutes moderate or substantial benefit (Dworkin 2008); older trials may only report participants with "any improvement". Newer trials tend to be larger, avoiding problems from the random play of chance. Newer trials also tend to be longer, up to 12 weeks, and longer trials provide a more rigorous and valid assessment of efficacy in chronic conditions. New standards have evolved for assessing efficacy in neuropathic pain, and we are now applying stricter criteria for inclusion of trials and assessment of outcomes, and are more aware of problems that may affect our overall assessment. To summarise some of the recent insights that must be considered in this new review:

  1. Pain results tend to have a U-shaped distribution rather than a bell-shaped distribution. This is true in acute pain (Moore 2011b; Moore 2011c), back pain (Moore 2010c), arthritis (Moore 2010b), as well as in fibromyalgia (Straube 2010); in all cases average results usually describe the experience of almost no-one in the trial. Data expressed as averages are potentially misleading, unless they can be proven to be suitable.

  2. As a consequence, we have to depend on dichotomous results (the individual either has or does not have the outcome) usually from pain changes or patient global assessments. The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) group has helped with their definitions of minimal, moderate, and substantial improvement (Dworkin 2008). In arthritis, trials shorter than 12 weeks, and especially those shorter than eight weeks, overestimate the effect of treatment (Moore 2009b); the effect is particularly strong for less effective analgesics, and this may also be relevant in neuropathic-type pain.

  3. The proportion of patients with at least moderate benefit can be small, even with an effective medicine, falling from 60% with an effective medicine in arthritis, to 30% in fibromyalgia (Moore 2009a; Moore 2010b; Straube 2008; Sultan 2008). A Cochrane review of pregabalin in neuropathic pain and fibromyalgia demonstrated different response rates for different types of chronic pain (higher in diabetic neuropathy and postherpetic neuralgia and lower in central pain and fibromyalgia) (Moore 2009a). This indicates that different neuropathic pain conditions should be treated separately from one another, and that pooling should not be done unless there are good grounds for doing so.

  4. Finally, presently unpublished individual patient analyses indicate that patients who get good pain relief (moderate or better) have major benefits in many other outcomes, affecting quality of life in a significant way (Moore 2010d).

Appendix 2. Search strategy for MEDLINE via Ovid

  1. exp PAIN/

  2. exp PERIPHERAL NERVOUS SYSTEM DISEASES/

  3. exp SOMATOSENSORY DISORDERS/

  4. FIBROMYALGIA/

  5. ((pain* or discomfort*) adj10 (central or complex or rheumat* or muscl* or muscul* or myofasci* or nerv* or neuralg* or neuropath*)).mp.

  6. (fibromyalgi* or fibrosti* or FM or FMS).mp.

  7. ((neur* or nerv*) adj6 (compress* or damag*)).mp.

  8. 1 or 2 or 3 or 4 or 5 or 6 or 7

  9. Imipramine/

  10. (imipramine or melipramine or Tofranil or Pryleugan or Janimine or Norchlorimipramine or Imizin).mp.

  11. 9 or 10

  12. 8 and 11

  13. randomized controlled trial.pt.

  14. controlled clinical trial.pt.

  15. randomized.ab.

  16. placebo.ab.

  17. drug therapy.fs.

  18. randomly.ab.

  19. trial.ab.

  20. groups.ab.

  21. or/13-20

  22. exp animals/ not humans.sh.

  23. 21 not 22

  24. 23 and 12

Contributions of authors

All authors contributed to writing the protocol.

LH and SD will search for studies, select studies for inclusion, and carry out data extraction. LH and RAM will carry out analyses. All authors will be involved in writing the review.

Declarations of interest

LH has no known conflicts of interest. SD, PW, and RAM have received research support from charities, government and industry at various times, but none related to this review. RAM and PW have consulted, and RAM has received lecture fees, from various pharmaceutical companies related to analgesics and other healthcare interventions in the last five years.

Sources of support

Internal sources

  • Oxford Pain Relief Trust, UK.

    General institutional support

External sources

  • No sources of support supplied