Abstract: One RCT of 22 participants with SCD, conducted in the USA was included in this review. Participants were randomly assigned to either pregabalin (n = 11) or placebo (n = 11). Oral pregabalin was administered at an initial dose of 75 mg twice daily. The drug was titrated at increments of 75 mg to a maximum of 600 mg daily or decreased by 75 mg per day if necessary, based on clinical presentation and pain level. Neuropathic pain was assessed using self-reports on the Leeds Assessment of Neuropathic Symptoms and Signs (S-LANNS) scale and the Neuropathic Pain Symptom Inventory (NPSI), where higher scores were indicative of more pain. Outcomes included self-reported pain, quality of life and withdrawal due to adverse effects measured at baseline and monthly for three months post-intervention. The overall risk of bias was low with a high risk of bias due to attrition. In relation to this reviews primary outcomes, for self-reported neuropathic pain relief, given the paucity of data, we are very uncertain whether there is a difference between the pregabalin and placebo groups at the end of three months as measured by the S-LANSS scale, mean difference (MD) -2.00 (95% confidence interval (CI) -9.18 to 5.18), or the NPSI scale, MD -11.10 (95% CI -33.97 to 11.77) (very low-quality evidence). There was no report of 'Patient Global Impression of Change' in the included trial. Although the mean quality of life scores (Short Form-36) at three months showed small increases in seven of the eight domains post-intervention in the pregabalin group as compared to the placebo group, this was very low-quality evidence and we are very uncertain whether pregabalin increases quality of life. Neither of our pre-defined outcomes of 'time to improvement of symptoms' or 'changes in sleep quality', were measured in the included trial. While treatment-related adverse effects appeared higher in pregabalin group than the placebo group at three months, this was very low-quality evidence and we are very uncertain whether there is a difference, RR 1.33 (95% CI 0.39 to 4.62) (very low-quality evidence). There was one withdrawal for adverse effects in the pregabalin group while three people withdrew or dropped out from the placebo group due to adverse effects and complications and hospitalisation related to SCD. The included trial provided very low-quality evidence. Self-reported pain relief was greater in the pregabalin group compared to the placebo control group but only using the S-LANSS scale and we are very unsure whether there is a difference. While the pregabalin group tended to have improved quality of life over the duration of the trial, this was very low-quality evidence and we are uncertain whether there is a difference. Adverse effects and withdrawals were similar across the treatment and placebo control group in trial. There are both insufficient trials addressing this review question and insufficient outcomes addressed in the single included RCT. Therefore, there is still a significant gap in evidence on interventions for neuropathic pain in people with SCD.

Plain-language summary: After a detailed search of scientific literature, we identified one trial that was eligible for inclusion. In this trial people with SCD who were diagnosed to have neuropathic pain were randomly put into groups to take either a drug named pregabalin or a placebo (no active medication) treatment. The trial was conducted in the USA and included 22 participants with SCD, with 11 people in the pregabalin group and 11 in the placebo drug group. Assessments were measured at baseline and monthly for three months. Self-reported neuropathic pain relief and quality of life scores (Short Form-36) were no different between the pregabalin and placebo groups. The outcomes of time to improvement of symptoms and changes in sleep quality were not measured in the included trial. Few unwanted effects were noted and the numbers of these were not different between participants who were given pregabalin versus those given placebo. In conclusion, the effect of pregabalin on SCD neuropathic pain was no different to placebo. We are unable to make firm conclusions regarding our objectives on the basis of a single small trial which only addressed three of our seven prespecified outcomes. Larger, well-conducted trials of different treatments for neuropathic pain in people with SCD need to be carried out. The evidence in this review was assessed as very-low quality. The single trial in this review lost more than 15% of participants to follow-up over three months. We downgraded the level of evidence due to lack of clarity in how the participants were assigned to the pregabalin or the placebo group and due to the small number of events and participants in the trial.