Venlafaxine for neuropathic pain

  • 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 venlafaxine for chronic neuropathic pain in adults.

  2. To assess the adverse events associated with the clinical use of venlafaxine for chronic neuropathic pain in adults.

Background

This protocol is based on a template for reviews of drugs used to relieve neuropathic pain. The aim is for all reviews to use the same methods, based on new criteria for what constitutes reliable evidence in chronic pain (Moore 2010a; Appendix 1).

Description of the condition

Neuropathic pain, unlike nociceptive pain such as toothache and osteoarthritis, is caused by nerve damage, often accompanied by changes in the central nervous system (CNS) (Iannetti 2005). It is by nature chronic and may be present for months or years. The 2011 definition of neuropathic pain is "pain caused by a lesion or disease of the somatosensory system" (Jensen 2011). Many people with neuropathic pain are significantly disabled, with 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% confidence interval (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). The prevalence of neuropathic pain was reported as being 3.3% in Austria (Gustorff 2008), 6.9% in France (Bouhassira 2008) and as high as 8% in the UK (Torrance 2006). Some forms of neuropathic pain, such as diabetic neuropathy and post-surgical chronic pain (which is often neuropathic in origin) are increasing (Hall 2008). Although incidence rates for neuropathic pain have not been accurately reported in Ireland, recent results from the PRIME study (Prevalence, Impact and Cost of Chronic Pain) suggest a prevalence of 36% for chronic pain in the community setting (Raftery 2011). It is likely that a significant proportion of these patients suffer from pain of neuropathic origin.

Neuropathic pain is known to be difficult to treat effectively, with only a minority of individuals experiencing a clinically relevant benefit from any one intervention. Thus it constitutes a significant burden on healthcare systems and society at large, as well as being distressing for individual patients (Moore 2013). A multidisciplinary approach is now advocated, with pharmacological interventions being combined with physical or cognitive interventions, or both. Conventional analgesics are usually not effective, although opioids may be in some individuals. Others may derive some benefit from topical lidocaine patches or topical capsaicin. Treatment is more usually by so-called 'unconventional' analgesics, such as antidepressants or antiepileptics.

Description of the intervention

The antidepressant agent venlafaxine is a serotonin reuptake inhibitor and weak noradrenaline reuptake inhibitor, but is not considered to affect other receptor systems. It is used in the treatment and prevention of recurrence of major depressive disorder, as well as in the treatment of generalised anxiety disorder, social anxiety disorder, panic disorder and agoraphobia. Although not licensed in Ireland (or the UK) for the treatment of chronic or neuropathic pain, it is commonly used for these indications. The drug is available as prolonged-release capsules (37.5 mg, 75 mg, 150 mg) suitable for once daily dosing. For the treatment and prevention of depression, the recommended starting dose for prolonged-release venlafaxine is 75 mg given once daily. Patients not responding to the initial 75 mg/day dose may benefit from dose increases up to a maximum dose of 375 mg/day. As with other serotonergic agents, serotonin syndrome, a potentially life-threatening condition, may occur as a side effect of venlafaxine treatment, particularly with concomitant use of other agents that may affect the serotonergic neurotransmitter system. Suicide-related behaviours, mydriasis (dilated pupils) and dose-related increases in blood pressure and heart rate have also been reported with venlafaxine. Other, more common, side effects include nausea, dizziness, drowsiness and dry mouth.

How the intervention might work

Venlafaxine is a chimeric compound and both R- and S-enantiomers, and their O-desmethylated metabolites, are reported to mediate inhibition of serotonin and noradrenaline reuptake (Bolden-Watson 1993; Muth 1986; Muth 1991). Its relatively clean pharmacological profile means that venlafaxine has a favourable adverse effect profile in comparison to other antidepressants used in pain management, especially the tricyclic antidepressants such as amitriptyline. The major metabolite, R-O-desmethylvenlafaxine, has been reported as the most potent inhibitor of both noradrenaline and serotonin reuptake (Muth 1991). Recently, this metabolite (desvenlafaxine) has been approved by the US Food and Drug Administration as a treatment for major depressive disorder (Seo 2010). Relating steady-state concentration of venlafaxine to in vitro reuptake inhibitory concentration suggests that serotonin reuptake is maximal at low doses (< 100 mg daily), whereas noradrenaline reuptake increases over the dose range of 100 mg to 375 mg/day. Inhibition of both serotonin and noradrenaline reuptake is thought to be important for the antidepressant activity of venlafaxine. However, the mechanism of action of venlafaxine in the treatment of neuropathic pain remains uncertain and is likely to differ from the mechanisms underlying its antidepressant effect. In animal experiments, venlafaxine-induced analgesia was reported to be mediated via adrenergic mechanisms and via the κ and δ opioid receptors (Schreiber 1999). It is important to note that there tends to be little or no correlation between the effect of antidepressants on mood and pain in humans and that antidepressants can produce analgesia in patients with and without depression (Onghena 1992). Furthermore, antidepressant-induced pain relief typically emerges more rapidly and at a lower dose than the antidepressant effect, which often takes up to six weeks.

Why it is important to do this review

Venlafaxine is a well-tolerated antidepressant and an established pharmacological intervention for chronic neuropathic pain. In a recent update to an earlier Cochrane review of antidepressants for neuropathic pain, preliminary evidence for the effectiveness of venlafaxine in relieving pain in polyneuropathy was reported (Saarto 2007). In animal studies, thermal hyperalgesia in rats with an induced mononeuropathy was relieved by venlafaxine (Lang 1996). Similarly in human experimental studies, the threshold at which repetitive electrical stimulation shows pain summation was reduced by venlafaxine (Enggaard 2001). Taken together, there is good justification for conducting a comprehensive systematic review to establish whether an evidence base exists for the clinical use of venlafaxine in neuropathic pain management. This review will be one of several updates to the Saarto 2007 review of antidepressants in neuropathic pain. It will apply more stringent criteria for validity and may include new studies that have emerged since the 2007 update by Saarto and Wiffen.

The standards used to assess evidence in chronic pain trials have changed substantially since 2008, because of an improved awareness of quality issues and the emergence of new recommendations by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT; Dworkin 2008). Particular attention is now being paid to trial duration, withdrawals and statistical imputation following withdrawal, all of which can substantially alter estimates of efficacy. The most important change is the move from using average pain scores, or average change in pain scores, to the number of patients who have a large decrease in pain (by at least 50%); this level of pain relief has been shown to correlate with improvements in comorbid symptoms, function and quality of life. These standards are set out in the reference guide for pain studies (AUREF 2012).

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 number needed to treat for an additional beneficial outcome (NNTB) 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 venlafaxine for chronic neuropathic pain in adults.

  2. To assess the adverse events associated with the clinical use of venlafaxine for chronic neuropathic pain in adults.

Methods

Criteria for considering studies for this review

Types of studies

We will include studies if they are randomised controlled trials (RCTs) with double-blind assessment of participant outcomes following two weeks of treatment or longer, though 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:

  • 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; and

  • spinal cord injury.

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.

Types of interventions

Venlafaxine at any dose, by any route, administered for the relief of neuropathic pain or 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. Patient-reported global impression of change (PGIC) much or very much improved.

  4. Patient-reported global impression of change (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.

  5. Withdrawals due to adverse events.

  6. Specific adverse events, particularly somnolence and dizziness.

Search methods for identification of studies

Electronic searches

We will search the following databases with a start date of January 1990:

  • 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. We will tailor the searches to the individual databases.

Searching other resources

We will review the bibliographies of any randomised trials identified and review articles, contact the authors and known experts in the field, and search www.clinicaltrials.gov to identify additional published or unpublished data. We will search the meta-Register of controlled trials (mRCT) (www.controlled-trials.com/mrct) and the WHO International Clinical Trials Registry Platform (ICTRP) (apps.who.int/trialsearch/) for ongoing trials.

Data collection and analysis

Selection of studies

We will determine eligibility by reading the abstract of each study identified by the search. We will eliminate studies that clearly do not satisfy the inclusion criteria and obtain full copies of the remaining studies. Three review authors (HCG, RMG and MCH) will read these studies independently and reach agreement by discussion. We will not anonymise the studies in any way before assessment. We plan to include a PRISMA study flow diagram in the full review (Liberati 2009), to document the screening process, as recommended in Part 2, Section 11.2.1 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

Data extraction and management

Three review authors (HCG, RMG and MCH) 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 as the basis for inclusion (Jadad 1996), limiting inclusion to studies that are randomised and double-blind as a minimum. We will use the 'Risk of bias' tool to assess the likely impact on the strength of the evidence of various study characteristics relating to methodological quality (randomization, allocation concealment, blinding, freedom from selective reporting), study validity (duration, outcome reporting, and handling of missing data) and size (Moore 2010c).

Two authors (HCG and RMG) 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. We will assess the following for each study:

  1. 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, e.g. 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 (e.g. 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 (e.g. 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 (e.g. 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, e.g. 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-blinded.

  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, used 'baseline observation carried forward' analysis or both); 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 numbers needed to treat to benefit (NNTBs) as the reciprocal of the absolute risk reduction (ARR) (McQuay 1998). For unwanted effects, the NNTB becomes the number needed to treat to harm (NNTH) 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). We will not use continuous data in analyses because it is inappropriate where there is an underlying skewed distribution. [Note from Anna: Andrew Moore et al prefer to stick to NNH and NNT, as stated in the template protocol. Happy for you to decide which format to use.]

Unit of analysis issues

We will split the control treatment arm between active treatment arms in a single study if the active treatment arms were not combined for analysis.

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. We will assign missing participants to 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 the 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 a NNTB 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 three 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 methods for drop-outs, report an ITT analysis, last eight or more weeks, have a parallel-group design and have at least 200 participants (preferably at least 400) in the comparison (Moore 1998; Moore 2010a; Moore 2012). We will report these top-tier results first. The second tier will use data from at least 200 participants, but where one or more of the above conditions is not met (for example, reporting at least 30% pain intensity reduction, using LOCF or a completer analysis, or lasting four to eight weeks). The third tier of evidence relates to data from fewer than 200 participants, or where there are expected to be significant problems because, for example, of very short-duration studies of less than four weeks, where there is major heterogeneity between studies, or where there are shortcomings in allocation concealment, attrition or incomplete outcome data. For this third tier of evidence, no data synthesis is reasonable, and may be misleading, but an indication of beneficial effects might be possible.

Subgroup analysis and investigation of heterogeneity

We will undertake subgroup analysis for:

  • dose of venlafaxine;

  • different painful conditions.

Sensitivity analysis

This may not be possible due to a small evidence base.

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 for 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 2011a; Moore 2011b), 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 DISORDERS/

3. exp SOMATOSENSORY DISORDERS/

4. ((pain* or discomfor*) adj10 (central or complex or rheumat* or muscl* or nerv* or neuralgia* or neuropath*)).mp

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

6. 1 or 2 or 3 or 4 or 5

7. Venlafaxine.mp.

8. 6 and 7

9. randomized controlled trial.pt.

10. controlled clinical trial

11. randomized

12. placebo.ab.

13. drug therapy.fs.

14. randomly.ab.

15. trial.ab

16. groups.ab

17. or/9-16

18. exp animals/ not humans.sh.

19. 17 not 18

20. 19 and 8

Contributions of authors

HCG registered the title, wrote the protocol and review, carried out searching, identified studies for inclusion and carried out data extraction. RMG and MCG identified studies for inclusion, carried out data extraction and assisted in drafting. DJB and MB provided clinical guidance and reviewed the protocol and review. The methods section is adapted from a template protocol for antidepressants in neuropathic pain devised by the PAPAS Cochrane Review Group. All authors contributed to the final draft of the protocol and approved this published version.

HCG will be responsible for updates.

Declarations of interest

The authors declare no conflict of interest.

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • Health Research Board, Ireland.

    (HG is funded by a Cochrane Fellowship)