Gabapentin May Top Pregabalin for Sciatica Pain

Pauline Anderson

October 17, 2018

Gabapentin tops pregabalin for pain reduction in patients with chronic sciatica, results of a head-to-head comparison show. But at least one expert has concerns about this conclusion.

In addition, gabapentin has fewer and less severe side effects, particularly those related to the central nervous system, compared with pregabalin.

"Clinicians need to be aware that these drugs are not the same; that there's a difference between the two medications that could impact patients," lead author Kelvin Robertson, BPharm and PhD candidate, Department of Pharmacy, Medical Services Group, Townsville Hospital, and adjunct senior lecturer, School of Medicine and Dentistry, James Cook University, Australia, told Medscape Medical News.

The study was published online October 15 in JAMA Neurology.

First Head-to-Head Comparison

The two anticonvulsants are both analogs of γ-aminobutyric acid (GABA).

"They are both very similar in chemical structure and mode of action. They both work on GABA, so they both basically stop pain signals getting to the brain. They also work on calcium channel blockers, so they regulate calcium channels in the nerve cells, and that decreases contraction of nerves and leads to less pain."

Both drugs are used to treat sciatica.

The study was "the first of its kind globally to compare these drugs head-to-head" in patients with chronic sciatica, said Robertson. This type of pain radiates into a leg to at or below the knee and lasts at least 3 months.

The single-center study included 18 adults with sciatica who had not previously received gabapentin or pregabalin.

Study participants received pregabalin first, then gabapentin, or vice versa, in a double-blinded fashion.

The starting dose of pregabalin was 150 mg once daily, which was titrated up to a maximum of 300 mg twice daily. Those taking gabapentin started at 400 mg once daily, which was titrated up to a maximum of 800 mg three times daily.

Patients took the medication three times a day. Those receiving pregabalin, typically dosed twice daily, received a placebo for the mid-day dose.

After a 4-week titration period, the maximum tolerated dose was maintained for 4 weeks before the first study medication was stopped for a 1-week washout period.

Participants received standard neurosurgical care and could use concomitant medications, including analgesics.

"These patients are in pain; we thought that it was unethical to have them stop all of their background therapies," said Robertson.

"We mitigated any risk of this having bias in our results by making sure that every patient coming into our trial was stable on their background therapy for at least 30 days before enrollment, and that during the trial, there were no changes to their background therapies, and if there were, this had to be relayed to the investigative team," he added.

Differing Side Effect Profile

The primary outcome was leg pain intensity using a visual analog scale (VAS). Participants were asked to rate their average leg pain during the last 24 hours on a 10-point scale, with zero representing no leg pain and 10 representing the worst pain imaginable.

The key secondary outcome was the Oswestry Disability Index (ODI) questionnaire, in which scores range from 0 to 100, with higher scores indicating greater disability.  

The original recruitment target was 38 patients, with an interim analysis planned at 50% sample size. However, the trial was stopped after predetermined criteria were met.

Of the 20 patients enrolled at that point, two from the gabapentin-first group were ultimately excluded from the analysis.

The results showed a significant mean VAS reduction for gabapentin (7.54 to 5.82; P < .001) and pregabalin (7.33 to 6.38; P = .002).

When unadjusted mean differences in VAS reduction were compared head-to-head, gabapentin proved superior (1.72 vs 0.94; P = .035).

As for disability, there was a significant reduction on the ODI for both gabapentin and pregabalin. When unadjusted mean differences were compared head-to-head, though, there was no significant difference (P = .63).

Frequency and severity of adverse events were measured on a 10-point scale, 10 being the worse possible score. There were 38 adverse events reported in 67% of patients.       

There were significantly more adverse events associated with pregabalin than gabapentin (81% vs 19%, P = .002).

For both drugs, adverse events were predominantly related to the central nervous system, such as drowsiness, dizziness, and vertigo.

However, gabapentin was associated with less severe adverse events than pregabalin (mean severity, 4.57 vs 6.35; P = .01).

It's not clear why outcomes for the two drugs were different. Robertson is hoping that further research with a larger sample will help determine "exactly what's happening here in terms of one drug producing more side effects compared with the other when they're basically structurally similar."

It's possible that pregabalin interacts with other neurotransmitters, which is causing more side effects, said Robertson.

The new results may have an impact on prescribing, he said. In Australia, pregabalin is on the pharmacy formulary, whereas access to gabapentin is more restricted.

"Now that we have shown that gabapentin is superior, we will be pressing to have it more freely available to patients in the community."

Concerns Raised and Addressed

Christine Lin, PhD, associate professor, Institute for Musculoskeletal Health, Sydney School of Public Health, University of Sydney, Australia, who has done extensive research in this area, commented on the study for Medscape Medical News.

Lin raised concerns about this new study, including its very small sample size and design. She noted that it is a comparison of two drugs that only provides data on whether there was a difference, and not whether either drug was effective.

The data presented in the article "don't quite support" the authors' conclusion that gabapentin was superior in pain reduction compared with pregabalin, said Lin.

For instance, the study does not report the average difference in pain reduction, she said.

"This is important because while the authors have reported a difference between groups statistically, they did not report how big or small this difference was for the average reader to make a judgment on whether the size of the difference is big enough to be worthwhile in clinical practice.

"We also don't know how precise the data are, so how confident we can be at the average difference between the groups," she said.

Lin explained that the authors reported a mean pain reduction of 1.72 on the 10-point pain scale in the gabapentin group versus 0.94 in the pregabalin group, with a significant difference between groups (P = .035), but notes this was based on the average difference between the groups (1.72 - 0.94 = 0.78).

Lin pointed out that the authors considered a 1.5-point difference to be worthwhile. "What they found was below that, so it is not correct to claim that gabapentin was superior to pregabalin," she said.

Robertson noted that the clinical significance was based on "an individual level," not the difference between the drugs. The 1.5 threshold was reached for patients on gabapentin but not on pregabalin using the VAS scale, he said.

Lin also noted that the trial was set up to compare gabapentin versus pregabalin, and not gabapentin or pregabalin versus no treatment or placebo.

"While we saw a favorable change with both gabapentin and pregabalin, this is what we call a 'within-group change' — the difference at the start versus at the end of treatment," she said.

"This is not a reliable way of detecting whether a treatment truly has provided a benefit."

For example, she added, study participants may have experienced natural recovery.

A placebo-controlled trial would be very difficult to conduct in patients with chronic sciatica in severe pain, such as those in the current study, said Robertson. A crossover design allowed the researchers to "examine the interchange" between the drugs, he said.

'Alarming' Picture Emerging

 

Another study by Lin's group showed that pregabalin was not significantly better than placebo in patients with sciatica and led to more side effects (N Engl J Med. 2017;376:1111-1120).

In addition, a meta-analysis showed that anticonvulsants are not effective for treating low back pain or lumbar radicular pain, and again, have a relatively high risk for adverse events (CMAJ. 2018;190:E786-E793).

Most clinical trials, especially those with such a small sample size as in the current study, aren't set up to detect differences in side effects, particularly serious ones, because they're relatively rare, said Lin.

But from larger studies, "an alarming picture" is emerging that shows that gabapentin and pregabalin have serious side effects, including the potential for misuse, especially when combined with opioids, and suicidal ideation, said Lin.

Funding for the study was provided by a grant from the Townsville Hospital Study, Research, and Education Trust. Robertson has reported no financial disclosures. Lin was the senior author of the New England Journal of Medicine study that found no difference in treatment effect between pregabalin and gabapentin. The medicines used in her study were provided by Pfizer, but she and the other investigators retained autonomy over the trial design, conduct, analysis, and reporting.

JAMA Neurol. Published online October 15, 2018. Abstract

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