Benefits and harms of drugs for “neuropathic” pain | Therapeutics Initiative – January 19, 2016
Chronic pain (at times presumed to be “neuropathic” in origin) is a common problem in clinical practice. It is now well recognized that the results of drug treatment are more often disappointing than no
Despite this, from 2005-2014 the number of British Columbians prescribed
- gabapentin increased 1.8 fold,
- pregabalin 17 fold, and
- duloxetine 3.6 fold (from 2008).
- Use of venlafaxine (mostly for depression/anxiety) has remained relatively stable.
In 2009 Therapeutics Letter 75 on gabapentin concluded:
- Gabapentin reduces neuropathic pain by < 1 point on a 0-10 point scale and benefits about 15% of carefully selected patients (NNT=6-8).
- A similar proportion of people suffer harm (NNH=8).
- A test of benefit/harm can be made after 1-2 days at a low dose (100-900 mg/day).
- Benefit is unlikely to increase with higher doses or longer treatment.
This Letter updates information on gabapentin and critically appraises randomized clinical trials (RCT) assessing the benefits and harms of three other drugs promoted for neuropathic pain: pregabalin, duloxetine, and venlafaxine. It is based primarily on 4 Cochrane reviews.
Although all pain metrics have limitations a 50% or greater reduction from a baseline pain score has been promoted as a more clinically relevant outcome for “neuropathic” pain because it correlates with improvements in comorbidity, function, and quality of life.
Using this outcome across all 4 Cochrane reviews, the mean number of people who must be treated for one to achieve a ≥ 50% reduction in pain (NNT) compared to placebo is about 6.
The greatest potential bias comes from the likelihood that patients and investigators were unblinded by observing drug adverse effects
almost all RCTs included in the Cochrane reviews were funded by drug manufacturers.
The evidence of benefit for tricyclic antidepressants for neuropathic pain is weaker and it is not possible to estimate a meaningful NNT
Withdrawals due to adverse effects compared with placebo were higher with gabapentin, pregabalin, duloxetine and venlafaxine
Approximately 80% of people receiving these drugs experienced at least one adverse effect. The most common were somnolence, dizziness, and nausea.
Anticholinergic effects, such as dry mouth and constipation, were common with duloxetine.
How soon is pain reduced?
In the majority of trials pain reduction compared with placebo was demonstrable within the first week. Very little additional pain reduction occurred after the second week.
Is there evidence that increasing dose improves response?
For gabapentin, pregabalin, duloxetine and venlafaxine, RCTs demonstrated little or no benefit from doses higher than the lowest dose that was superior to placebo
Evidence from 8 Cochrane reviews should temper expectations regarding the likelihood and magnitude of pain relief from gabapentin, pregabalin, duloxetine, venlafaxine, amitriptyline, nortriptyline, imipramine or desipramine.
When initiating a therapeutic trial with one of these drugs in a patient, it is reasonable to start at the lowest recommended dose and assess the patient for benefit and harm at 1 week.
- The evidence base for drug treatment of neuropathic pain is weak, due to the small magnitude of clinically meaningful effects and the high risk of bias in the RCTs. (See Why Most Published Research Findings Are False)
- Probably less than 1 in 10 patients achieve a meaningful reduction in pain.
- Most patients experience some adverse side effects like somnolence, dizziness, nausea, dry mouth and constipation.
- To identify patients who respond, a therapeutic trial with early assessment is essential. Reassessment of drug utility is needed to detect people with spontaneous remission or placebo response.
- Higher doses are unlikely to achieve greater pain reduction, but are more likely to cause harm.
Despite so few positive and so many negatives, the CDC insists such non-opioid medications are “better” than opioids for pain.
In light of research results, this is just ridiculous.