chronic pelvic pain: gabapentin ineffective

 A recent study found that gabapentin was not effective for chronic pelvic pain in women (see chronic pelvic pain gabapentin not help Lancet2020 in dropbox, or doi.org/10.1016/S0140-6736(20)31693-7)

 

Details:

--306 women with chronic pelvic pain (defined as pain within the true pelvis), with or without dysmenorrhea or dyspareunia, were randomized to gabapentin (up to 2700mg/d) vs placebo for 16 weeks, study done in 2015-19 in 39 UK hospital centers 

-- inclusion criteria: age 18 to 50, no obvious pelvic pathology at laparoscopy (e.g. macroscopic endometriosis, complex ovarian cyst, ovarian cyst >5 cm, fibroids >3 cm, and dense adhesions)

-- dosing regimen: initially 1 capsule (300 mg) daily, increased by 1 capsule every 3 days until the participant perceived adequate pain relief or had side effects, with the goal to maintain the highest tolerated dose until the end of week 16

-- oral opioids and antidepressants were allowed

-- primary outcomes: worst and average pain scores assessed separately on a numerical rating scale (NRS). Pain scores were collected weekly over a four-week period, since pelvic pain can fluctuate during a woman’s menstrual cycle (so that measuring at a single point of time might inaccurately reflect true pain scores)

-- secondary outcomes: at 16 weeks, the proportion of women who had a 30-50% reduction in worst and average pain scores; global patient impression of change; general quality of life (Short Form-12); other pain assessment (Brief Pain Inventory); assessment of neuropathic-like features of pain (PainDETECT), and other questionnaires assessing psychological distress, pain-related cognitions, impairments in paid work activities, and sexual functioning

-- the NRS pain scale (numerical rating scale) minimal clinical significance was a change of 1 point representing minimal or little change, and 2.0-2.7 points reflecting much or some change

-- adverse outcomes were assessed by patient self-report

-- 90% adherence to meds found in both groups

-- overall median dose taken daily: 2100 mg in both groups, though it did reach 2700 mg in future weeks for some women

 

Results:

--mean worst pain, by NRS:

    --gabapentin: 7.1, difference from baseline was -1.4

    --placebo: 7.4, difference from baseline was -1.2

    --adjusted mean difference was -0.20 (-0.81 to 0.42), p=0.47. Not nearly statistically or clinically significant

--mean average pain, by NRS:

    --gabapentin: 4.3, difference from baseline was -1.1

    --placebo: 4.5, difference from baseline was -0.9

    --adjusted mean difference was -0.18 (-0.71 to 0.35), p=0.45. Not nearly statistically or clinically significant

-- use of painkillers: fewer in women on gabapentin, but not statistically significant

    -- by breakdown of painkillers, gabapentin vs placebo: 55% vs 59% used rescue medication; 40% vs 45% used NSAIDs, 55% vs 42% used opiates [interesting that opiates we used more often in those on gabapentin….]

-- secondary outcomes: they did not comment at all about the patient reported questionnaires, but my review of their table found that at the end of the study, there were no real significant differences in any of them

--serious adverse events:

    --gabapentin: 10 (7%), especially dizziness (54% vs 28%), drowsiness (52% vs 29%), and visual disturbances (22% vs 11%)

    --placebo: 3 (2%)

    --difference significant, with p=0.04

 

Commentary: 

--chronic pelvic pain is common, affecting 2-24% of women worldwide, and associated with reduced quality of life and work productivity 

--55% of women have no obvious cause for the pain by laparoscopy 

--off-label use of gabapentin for women with chronic pelvic pain has increased, perhaps because there are no established treatments 

--gabapentin is often used for chronic pain syndromes, the most studied being for neuropathic pain, and is supported by a Cochrane review from 2017 (see gabapentin helps chronic neurop pain cochrane 2017 in dropbox, or DOI: 10.1002/14651858.CD007938.pub4) for neuropathic pain, and it is the 3rd choice by the American Diabetes Association in their 2020 Diabetes Care Guidelines for diabetic neuropathy (see https://gmodestmedblogs.blogspot.com/2020/02/new-diabetes-guidelines-2020.html ) 

    --however, there have been impressive recent systematic reviews/metanalyses that have found the gabapentinoids (gabapentin and pregabalin) are ineffective:

    --one systematic review/meta-analysis of 9 trials did not find that pregabalin or gabapentin were helpful in patients with low-back or radicular pain (see http://gmodestmedblogs.blogspot.com/2018/07/gabapentinoids-still-not-help-low-back.html )

    --another assessed diabetic peripheral neuropathy specifically, a systematic review of 21 RCTs on pregabalin or gabapentin, finding either no effect (5 RCTs for gabapentin) or a small effect (16 RCTs, low strength of evidence, for pregabalin): see http://gmodestmedblogs.blogspot.com/2017/04/diabetic-peripheral-neuropathy-and-more.html , with much better results for other meds (eg duloxetine, venlafaxine, tricyclics)

-- and, gabapentin is associated with significant adverse consequences:

     -- there has been a dramatic increase in gabapentin overdoses, and it is associated with respiratory depression as well as being a substance with high misuse/diversion potential (see http://gmodestmedblogs.blogspot.com/2020/01/gabapentin-and-baclofen-overdoses.html ).

    -- there also may be a higher opioid death rate when opioids are used in combination with gabapentinoids (despite prior CDC suggestions to add them to opioids as an adjunctive therapy to decrease opioid use, see http://gmodestmedblogs.blogspot.com/2018/09/gabapentanoids-plus-opioids-higher.html

    --and, gabapentin is the 10^thmost commonly prescribed medication....

-- this study found no significant difference from gabapentin in either worst or average NRS pain scores at 13 to 16 weeks after randomization. And no difference in the myriad of secondary outcomes measured. And this was with a pretty hefty dose of gabapentin

Limitations of study:

-- though this was a randomized controlled trial, a problem with gabapentin is that it has lots of adverse effects, effectively unblinding the trial (a general issue in RCTs when the med has common adverse effects: patients tend to know whether they are on med vs placebo). 

    --however, in this study 74% of women correctly guessed they were on placebo and 58% correctly guessed they were on gabapentin (the latter not much different from chance). And, there was no difference in taking other medications for pain, suggesting that in this case there was minimal significant bias

-- as with pain studies in general, they rely on self-reports by patients, not an objective measurement, and patients have very different pain thresholds (not assessed).

-- they also did not include important psychosocial variables, such as domestic violence, which is more frequently found in those with pelvic pain

-- and, this was a relatively short study (16 weeks); would be great to know the longer term effects

 

So, though studies are somewhat mixed, this study adds another negative in terms of gabapentin benefit for pain. And, we know that gabapentin, though prescribed very frequently, is not a benign drug. Pain in general is a very subjective experience and is one of the outcomes that has the highest placebo effect. As noted in many prior blogs including the recent one on low back pain with sciatica, nonpharmacologic therapy is often quite successful and much healthier than pain meds (see http://gmodestmedblogs.blogspot.com/2020/10/sciatica-early-pt-helps-longterm.html ). and, if meds are needed, there are others that are safer and apparently more effective...

geoff

 

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