pregabalin did not help sciatica

​A recent Australian RCT found no significant effect for pregabalin in patients with acute or chronic sciatica (see sciatica pregabalin ineffective nejm2017 in dropbox, or Mathieson S. N Engl J Med 2017: 376: 1111).

Details:

-- 207 patients were randomized to pregabalin initially at a dose of 150 mg per day, adjusted to a maximum of 600 mg per day versus placebo for 8 weeks

-- sciatica was defined as radiating pain to one leg below the knee, accompanied by nerve root or spinal nerve involvement as indicated by at least one of dermatomal leg pain, muscular weakness, sensory deficits, or diminished reflex. The sciatica had to be present for a minimum of one week and a maximum of one year, and considered at least moderate in intensity or had resulted in at least moderate interference with daily activities

-- mean:  55% female, 53 yo, dermatomal pain in 85%, motor deficits in 30%, neurologic deficits in 35%, sensory deficits in the 4%, pain in both legs in 8%, pain on straight leg raising in 63%, clinical level of spine causing problems S1 in 50% /L5 in 33%/L4 in 22%/S2 in 10%/more than one level in20%, PainDETECT <12 in 45% (which suggests that a neurologic component was unlikely)/13-18 in 25% (neurologic component unclear)/greater than 18 in 25% (neurologic component likely). Mean duration of leg pain was 63 days.

-- the primary outcome was  leg pain intensity, measured on a 10 point scale, 0 being no pain and 10 worst pain; secondary outcome was the extent of disability, back pain intensity, and quality of life measures. Measurements were made at 8 weeks and at one year.

Results:

-- 74% of patients in each group were considered to have adhered to the dosing schedule, defined as taking at least 80% of their prescribed trial regimen.

-- at week 8, the mean unadjusted leg pain intensity score was 3.7 in the pregabalin group and 3.1 in placebo group, nonsignificant

-- at week 52 the mean unadjusted leg pain intensity score was 3.4 in the pregabalin group and 3.0 in placebo group, nonsignificant

-- no significant differences were observed with respect to any of the secondary outcomes at either week 8 or 52, including either physical or mental components of quality of life scores, global perceived effect, or extent of disability. Also there was no difference in the number of hours that the patients were absent from work over the year, the percentage of patients who used additional medications pain, or the percentage of patients who used health services.

-- Post hoc analysis showed that the duration of leg pain did not modify the effect of pregabalin [though most of the patients had sciatica for less than 3 months, so were not in the chronic category.]

-- 227 adverse events reported in the pregabalin group and 124 in the placebo group, with dizziness being the most common in the pregabalin group (70 events versus 19)

Commentary:

-- I am not sure how to reconcile the baseline PainDETECT scores, which suggests that a neurologic component to the pain was most likely present in only 25% or so, with the reported 63% having pain on straight leg raising, 44% having a sensory deficit, 30% with a motor deficit and 35% with a neurologic deficit. This PainDETECT tool is a validated questionnaire which basically includes all of the regular subjective questions for radicular pain (as documented appropriately in the study above) and their intensity, and does not include the physical exam, which, as in the above study, found many patients with significant deficits and positive straight leg raising sign. But all of the patients sounded clinically like they had neuropathic pain and were likely to be treated as such (as above, all of them had: "radiating pain to one leg below the knee, accompanied by nerve root or spinal nerve involvement as indicated by at least one of dermatomal leg pain, muscular weakness, sensory deficits, or diminished reflex"). And, when the researchers did control for the PainDETECT score, they did not find that it modified the results. 

-- One limitation of the study was that most patients had relatively short-term symptoms of sciatica, and three quarters of patients spontaneously have resolution of symptoms within 3 months (see the review article sciatica review nejm2015 in dropbox, or Ropper AH. N Engl J Med 2015; 372: 1240)

-- So, my sense is that, based on this study, it seems that pregabalin had no benefit for patients who might present to us in primary care with clinical acute-to-chronic sciatica.  Which raises a very real and common clinical dilemma: what is the best way to treat such a patient???? Though this study undercuts a potential role for the medication pregabalin, are there other meds targeted for neuropathy which might work, such as tricyclics or duloxetine/venlafaxine?? Unfortunately, the data are quite meager regarding the use of nonpharmacologic interventions in those with radicular pain (see the Ropper article referenced above), including physical therapy, spinal manipulation, exercises, yoga/back strengthening exercises, etc, though there are better data supporting some of these for regular old low back pain. Since patients with sciatica do better with activity than rest, it does seem reasonable to provide analgesia to allow the patient to do more activity (though unproven). And, though not mentioned in this Ropper review, are some of the more recently described nonpharmacologic interventions used in non-neuropathic pain: see  blog http://gmodestmedblogs.blogspot.com/2017/03/internet-based-improvement-in-knee-pain.html  which also includes links to several other blogs supporting the utility of tai chi, mindfulness stress reduction, cognitive behavioral therapy. Bottom line: we just do not have great meds for chronic pain, these nonmedical interventions do seem to help for chronic pain, and they may be worth trying (and studying) for neuropathic pain.

-- And, this dearth of information for treatment of sciatica from well-conducted studies does point to a fundamental problem in our medical research approach: we (ie drug companies, with some governmental/public support) spend huge amounts of resources to develop (really expensive) meds for rare diseases, yet some common and really disabling conditions (eg sciatica) are not investigated rigorously, especially for nonpharmacologic interventions, but also for existing meds (there is not much incentive to test an already-approved drug like pregabalin, since it is probably already being prescribed widely, so the downside of a negative study for the drug company is much greater than the upside of a positive study).