LakkaPapadodima E. Venlafaxine HCl in the treatment of painful peripheral diabetic neuropathy, Venlafaxine in treatment of painful peripheral diabetic neuropathy. All studies included adults aged 18 years and above. We reviewed the bibliographies of any randomised trials identified and review articles, contacted authors of one excluded study and searched www.clinicaltrials.gov to identify additional published or unpublished data. All participants had metabolically stable diabetes (type I or type II). We planned to undertake subgroup analysis for: This was not possible due to a small evidence base. Systematic Reviews in Pain Research: Methodology Refined. However, effects on ongoing pain intensity (VAS 0 to 10), activities of daily living, adverse effects, and global efficacy and tolerance were also reported. Three review authors independently extracted data using a standard form and assessed study quality. However, many of these were small case reports, were of insufficient treatment duration, were openlabel studies, or involved other pain syndromes. The https:// ensures that you are connecting to the Pritchett YL, In the largest study by Rowbotham, 2004, 56% of participants receiving venlafaxine 150 to 225 mg achieved at least a 50% reduction in pain intensity versus 34% of participants in the placebo group and the number needed to treat for an additional beneficial outcome was 4.5. Selecting patients based on the runin period forces differential representation of certain subpopulations relative to others (Berger 2003). Forssell 2004 asked participants about 10 adverse effects (urination difficulties, fatigue, appetite, dry mouth, constipation, sweating, nightmares, nausea, headache, and palpitations) and asked participants to self evaluate the overall severity of these adverse effects on a 100mm VAS. Yucel B, Masand PS, This is true in acute pain (, Therefore, we have to depend on dichotomous results (the person either has or does not have the outcome) usually from pain changes or participant global assessments. Selection bias was assessed by reviewing details of the randomisation of participants to study groups and the allocation concealment procedures. 6. In accordance with most Cochrane reviews completed by the Pain, Palliative and Supportive Care Review Group (PaPaS), we included only randomised doubleblind studies in an effort to limit the potential for bias. A multidisciplinary approach is now advocated, with pharmacological interventions being combined with physical or cognitive interventions, or both. Neuropathic pain is difficult to treat effectively, with only a minority of individuals experiencing a clinically relevant benefit from any one intervention. We found six randomised, doubleblind trials of at least two weeks' duration eligible for inclusion. et al. NNTH was not significantly different. Sohi MS, Sit D, The phase IV clinical study analyzes which people take Viagra and have Peripheral neuropathy. It is likely that a significant proportion of these people have pain of neuropathic origin. Smart TS, Rice AS, Effexor XR (venlafaxine) is a prescription drug that's used to treat certain mental health conditions, such as major depressive disorder. Did not exclude neuropathic pain but most participants did not have neuropathic pain, Article was retracted in 2009 due to falsification of data, Venlafaxine arm was an uncontrolled study. This may reflect improved diagnosis, or it may be due to increased incidence of diabetesassociated neuropathy, linked to increasing levels of obesity. The site is secure. Gender data were reported for the 18 participants for whom data were analysed (6 men and 12 women). 2 participants excluded due to noncompliance, Random sequence generation (selection bias), Randomisation was performed by WyethLederle, who supplied the drug and placebo capsules 'using computergenerated numbers', Participants were allocated consecutively, Blinding of participants and personnel (performance bias), Identical capsules were supplied by a pharmaceutical company (WyethLederle), Blinding of outcome assessment (detection bias), 'The randomization code was not opened during the trial' and along with plasma concentration data were 'kept separate from investigators carrying out the assessments until the database was closed', Completer analysis was employed. Both Tasmuth 2002 and Forssell 2004 had a greater than 10% dropout rate and only reported data for participants who completed trials and, therefore, we assessed them as being at high risk of bias. Bell RF, In the study by Jia 2006, there was a relatively small dropout rate of less than 10% in the venlafaxine group, which reduced the attrition bias compared with other studies. et al. Daily activity scores were also not significantly different between groups while participant satisfaction was significantly higher in the venlafaxine 75 mg group compared with placebo. The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) group has helped with their definitions of minimal, moderate, and substantial improvement (, The proportion of people 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 (, Presently, unpublished individual participant analyses indicate that people who get good pain relief (moderate or better) have major benefits in many other outcomes, affecting quality of life in a significant way (, {"type":"entrez-nucleotide","attrs":{"text":"CD011091","term_id":"30327829"}}. Moore RA, Of the six included studies, five had fewer than 200 participants, and the largest study employed LOCF analysis and was only of six weeks' duration (Rowbotham 2004). Six participants withdrew from 66 who commenced on venlafaxine, and four of these withdrawals were due to adverse effects (one participant with severe gastrointestinal disturbance, one participant with palpitations, and two participants with moderate gastrointestinal disturbance). Inclusion in an NLM database does not imply endorsement of, or agreement with, Mechanism of Action Venlafaxine works by increasing serotonin levels, norepinephrine, and dopamine in the brain by blocking transport proteins and stopping their reuptake at the presynaptic terminal. Yucel 2005 performed a randomised doubleblind, placebocontrolled parallel trial with 60 participants with neuropathic pain assigned to venlafaxine 75 mg, venlafaxine 150 mg, or placebo for eight weeks. Depression and anxiety scores were also reported in some, but not all, of the reviewed studies. Furthermore, antidepressantinduced pain relief typically emerges more rapidly and at a lower dose than the antidepressant effect, which often takes up to six weeks. The 2011 definition of neuropathic pain is "pain caused by a lesion or disease of the somatosensory system" (Jensen 2011). Adverse effects and use of escape medication, 1week baseline observations. These six studies reported on 460 participants. Compromised blinding would have overestimated the effects of venlafaxine. Although these differences were not considered statistically significant, it is possible that participants may have correctly anticipated which treatment they received (and personnel may have guessed what patients were receiving) and blinding may not have been maintained throughout the study. However, only mean data were reported and it is unclear how many participants benefited from treatment. We analysed data for each painful condition in three tiers, according to outcome and freedom from known sources of bias. We found little compelling evidence to support the use of venlafaxine in neuropathic pain. Tasmuth T, As with other serotonergic agents, serotonin syndrome, a potentially lifethreatening condition, may occur as an adverse effect of venlafaxine treatment, particularly with concomitant use of other agents that may affect the serotonergic neurotransmitter system. 33/40 participants completed all 3 arms of study. Only two studies had more than 50 participants per treatment arm and four studies were significantly smaller than that and therefore presented a high risk of bias on the basis of size. All SNRIs work in a similar way and generally can cause similar side effects, though some people may not experience any side effects. Other types of neuropathic pain include postherpetic neuralgia, trigeminal neuralgia, and neuralgia caused by chemotherapy. 1) Berger VW, Rezvani A, Makarewicz VA. Turk DC, Similarly in human experimental studies, venlafaxine reduced the threshold at which repetitive electrical stimulation showed pain summation (Enggaard 2001). DOI: 10.1002/14651858.CD011091.pub2, 3) Rowbotham MC, Goli V, Kunz NR, Lei D. Venlafaxine extended release in the treatment of painful diabetic neuropathy: a doubleblind, placebocontrolled study. The study involved participants from the USA, Placebo, venlafaxine 75 mg, or venlafaxine 150225 mg/day for 6 weeks, followed by 2week tapered dose reduction, Primary outcome measures were VASPI, VASPR, CGIS and CGII, all of which were assessed by clinicians, 42 withdrawals in total (12/81 placebo arm; 12/81 venlafaxine 75 mg arm; 18/82 venlafaxine 150225 mg arm). Baseline pain score by VRS (07), median 3 (range 3 to 4) and baseline depression score by BDI (063), median 10 (range 1 to 28). 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). British Journal of Clinical Pharmacology 2008;66(2):26675). Rowbothams results may not be applicable for the clinician considering venlafaxine for a patient with severe neuropathic pain, and/or patients who require other analgesics. Moore RA, Gammaitoni A. Numbersneededtotreat analyses do timing, dropouts, and outcome matter? Risk of bias summary: review authors' judgements about each risk of bias item for each included study. Any painrelated outcome indicating some improvement. Direct effect on validity of response runin selection in clinical trials. Although all of the included studies were considered third tier evidence, we focussed our attention to Rowbatham (2004) because it was the largest, randomized, parallel designed study included in this review. Moore RA, Although not licensed in Ireland (or the UK) for the treatment of chronic or neuropathic pain, it is commonly used for these indications. Experimental pain scores were not considered for this review. Cleeland CS, Some people may need to start at a lower dose of 37.5 mg daily and then increase to 75 mg by mouth daily after 4 to 7 days once they have adjusted to the medication. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The most important change is the move from using mean pain scores, or mean change in pain scores, to the number of people who have a large decrease in pain (by at least 50%); this level of pain relief correlates with improvements in comorbid symptoms, function, and quality of life. HCG registered the title, wrote the protocol and review, carried out searching, identified studies for inclusion, and carried out data extraction. Tasdemir N, Use of escape medication in pain trials is considered a secondary outcome measure and two of our included studies reported that venlafaxine reduced the usage of alternative analgesics during the study period, which gives some weak indication of potential efficacy in treating neuropathic pain. National Library of Medicine et al. Katusic S, Therefore, we suggest revising the conclusions to: When considering venlafaxine for the treatment of neuropathic pain, it is important to recognize that certain patient populations were not included in the studies, and that the NNT is likely to be higher than reported (for 50% pain reduction) in return for potential for harm. The antidepressant agent venlafaxine is a serotonin reuptake inhibitor and weak noradrenaline reuptake inhibitor. Iyengar S, We planned to include a 'Summary of findings' table as set out in the author guide (AUREF 2012), but there were insufficient data. Moyer JA, government site. The first tier intended to 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 LOCF or other imputation methods for dropouts, report an ITT analysis, last eight or more weeks, have a parallelgroup design, and have at least 200 participants (preferably at least 400) in the comparison (Moore 1998; Moore 2010a; Moore 2012). This nerve damage can lead to burning pain, paresthesia (a feeling of pins and needles), weakness, and numbness (loss of sensation). The other three participants withdrew while in the nonvenlafaxine arm. Lee AJ. Muth EA, Pooled analysis of two randomized, placebocontrolled chronic low back pain trials. Global impression of improvement did not differ significantly between venlafaxine and placebo (8/16 placebo; 13/16 venlafaxine 75 mg; 1/14 venlafaxine 150 mg), 5/60 withdrew: 1 placebo; 1 venlafaxine 75 mg; 3 venlafaxine 150 mg, < 10% of participants did not complete the trial, Study appeared unblinded. Five of six studies were of short duration and four were of crossover design. Drugs that are commonly used to treat pain, such as paracetamol, ibuprofen, or morphine, are not very good at treating neuropathic pain. Sindrup SH. Venlafaxine is a reasonably welltolerated antidepressant and is a serotonin reuptake inhibitor and weak noradrenaline reuptake inhibitor. Overall, there is currently an inadequate amount of information available to warrant any change in current prescribing practice and we cannot recommend venlafaxine as a firstline treatment for neuropathic pain. An official website of the United States government. Derry S, Husbands GE, Moore RA, Larger, prospective welldesigned studies are required to provide more definitive conclusions on the efficacy of venlafaxine for treating neuropathic pain. They withdrew two participants due to noncompliance and one of these dropouts was reported as being due to lack of efficacy. Accessibility We searched the following databases with a start date of January 1990, because there are no earlier clinical trials of venlafaxine, which was developed in the late 1980s. A restricted search in May 2017 did not identify any potentially relevant studies likely to change the conclusions. Summary: Peripheral neuropathy is found among people who take Viagra, especially for people who are male, 50-59 old. University College Dublin, School of Medicine and Medical Science, Conway Institute, Belfield, Dublin 4Ireland, Princess of Wales Hospital, Cathedral Medical Centre, Lynn Road, ElyCambridgeshireUK, CB6 1DN, The University of British Columbia, Midwifery Program, Department of Family Practice, B54 2194 Health Sciences Mall, VancouverBCCanada, V6T 1Z3, Mater Misericordiae Hospital, Department of Anaesthesia, Eccles Street, Dublin 7Ireland, Trinity College Dublin, Centre for the Practice of Pharmacy, School of Pharmacy and Pharmaceutical Sciences, DublinIreland, Dublin 2. postoperative or traumatic neuropathic pain; chemotherapy/radiotherapyinduced neuralgia; human immunodeficiency virus (HIV) neuropathy; and. For example in this study, patients that had resistant or severe pain requiring more than one dose of analgesic would have been excluded. The absence of publication bias, whereby studies showing a lack of efficacy for venlafaxine are performed but not published, cannot be proven. All studies used completer analysis or LOCF analyses so that only those with greater than 90% completion were not at risk of attrition bias. That might make their use inappropriate in primary care, but at the same time their use may not be precluded in specialist care. 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 dropout, should be adopted to provide firsttier evidence in future trials. Of these, 242 were treated and 202 completed the study. Only one trial was both parallel design and placebocontrolled. However, while some doctors prescribe antidepressants in people with neuropathic pain, their benefits have not been confirmed in large clinical trials. Particular attention is now being paid to trial duration, withdrawals, and statistical imputation following withdrawal, all of which can substantially alter estimates of efficacy. 1 lost to followup, Authors stated that 'assignment to one of six possible treatment sequences was random via a computergenerated randomization code' and that this 'randomization plan was generated by one author who was not involved in the conduct of the trial', Participants were numbered consecutively. Andersen OK, We planned to use intentiontotreat (ITT) analysis where the ITT population consisted of participants who were randomised, took at least one dose of the assigned study medication, and provided at least one postbaseline assessment. D'Souza D, Enriched enrollment: definition and effects of enrichment and dose in trials of pregabalin and gabapentin in neuropathic pain. We only included studies with full journal publication. Sturkenboom MC. Further research studies on the mechanism of action of venlafaxine in treating neuropathic pain are also warranted. Since the two largest of the included studies only looked at diabetesassociated neuropathy (Jia 2006; Rowbotham 2004), and overall more than 80% of included participants had diabetes, it is possible that any benefits shown for venlafaxine may not be applicable to other painful neuropathic conditions. ((neur* or nerv*) adj6 (compress* or damag*)).mp. Therefore, this review has now been stabilised following discussion with the authors and editors. Derry S, Gaskell H, At least moderate pain relief was reported in 8/30 participants taking venlafaxine compared with 2/29 participants in the placebo arm of the study. In three studies (Forssell 2004, Jia 2006 and Tasmuth 2002), only mean data were reported. Four of the six studies reported some positive benefit for venlafaxine. Anxiety and depression scores were unaffected by either venlafaxine or placebo. Moore RA. Raftery MN, The drug is available as prolongedrelease capsules (37.5, 75, and 150 mg) suitable for once daily dosing. No significant difference between groups in anxiety (STAI) or depression (BDI), 10 dropouts including 8 due to adverse effects. We included randomised, doubleblind studies of at least two weeks' duration comparing venlafaxine with either placebo or another active treatment in chronic neuropathic pain in adults. Admittedly, the arrangements for blinding in this trial were complex. Kalso E, Gammaitoni AR, Pain results tend to have a Ushaped distribution rather than a bellshaped distribution. Random sequence generation (checking for possible selection bias). The same authors reported that 10% of placebo, 9% of venlafaxine 75 mg and 12% of venlafaxine 150 to 225 mg groups had a serious adverse effect, although their precise nature was unclear. This medication has been found to counter SSRI-induced sexual dysfunction, boost sexual drive and arousal, and increase the intensity or duration of an orgasm. However, if only combined data for both periods were reported, we drew attention to the possible bias associated with interpretation of this data. We also used the 'Risk of bias' tool to assess the likely impact on the strength of the evidence of various study characteristics relating to methodological quality (randomisation, allocation concealment, blinding, freedom from selective reporting), study validity (duration, outcome reporting, and handling of missing data), and size (Moore 2010b). During the baseline twoweek period, their pain intensity was measured as at least 40 on the 0 to 100 VAS scale. Furthermore, in future clinical studies it would be most beneficial if mean data were not reported so that proper estimates can be made of the proportion of participants benefiting from venlafaxine treatment. A further confounding factor was the complex interaction between depression and pain as venlafaxine is an established and effective antidepressant drug and not all studies measured depression at baseline or accounted for the fact that relief of depression may have a positive benefit on pain scores. Paine J, Mico JA, However, this study was subject to significant selection bias. We planned to 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 NNTB of 10 or higher) (Moore 2008). Outcome matter ( 6 men and 12 women ) the 18 participants for whom data were reported the. Clinically relevant benefit from any one intervention while some doctors prescribe antidepressants in with. Generation ( checking for possible selection bias similar side effects, though some may. We analysed data for each painful condition in three studies ( Forssell 2004, Jia 2006 and 2002. 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