Results Summary
What was the research about?
Cryptogenic sensory polyneuropathy, or CSPN, is a health problem that causes pain, numbness, and tingling. Pain is one of the worst symptoms of CSPN. Doctors can prescribe different medicines to treat CSPN pain, but few studies have compared how well these medicines work.
In this study, the research team compared four pain medicines for patients with CSPN: nortriptyline, duloxetine, pregabalin, and mexiletine. The team looked at how beneficial the medicines were by seeing if patients
- Reported that pain was 50 percent less than before taking the medicine
- Kept taking the medicine
- Avoided side effects
What were the results?
Based on pain reduction and patients being able to keep taking the medicine, nortriptyline and duloxetine had the highest benefit, followed by pregabalin and mexiletine.
Of the patients taking nortriptyline,
- 25 percent had pain reduced by half
- 38 percent stopped taking it
- 56 percent had side effects
Of the patients taking duloxetine,
- 23 percent had pain reduced by half
- 37 percent stopped taking it
- 47 percent had side effects
Of the patients taking pregabalin,
- 15 percent had pain reduced by half
- 43 percent stopped taking it
- 40 percent had side effects
Of the patients taking mexiletine,
- 20 percent had pain reduced by half
- 58 percent stopped taking it
- 39 percent had side effects
Patients taking mexiletine reported the least fatigue and the lowest amount that pain interfered in their lives. All four medicines improved patients’ physical and mental health but didn’t change how much pain interfered with their sleep.
Who was in the study?
The study included 402 patients with CSPN receiving care at one of 40 clinics across the United States. Of these, 85 percent were white, 7 percent were black, 4 percent were Asian, 4 percent were other or unknown races; 6 percent were Hispanic. The average age was 60, and 53 percent were men.
What did the research team do?
The research team assigned patients by chance to take one of the four medicines. Patients filled out surveys at the start of the study and again one, two, and three months later. The research team scored each medicine on its overall benefit. Higher scores meant a medicine worked better to decrease pain and fewer patients stopped taking it.
Patients with CSPN, caregivers of patients with CSPN, and members of a national neuropathy advocacy group helped with the study design. CSPN patients helped make sure the research focused on what was most important to patients. They also gave input on how to help patients stay in the study.
What were the limits of the study?
The research team scored medicines as less beneficial if a patient stopped taking them for any reason. The main reasons that patients stopped taking pregabalin was because it cost much more than the other medicines. Scores might have been different if the team separated out reasons for not taking a medicine. Also, the team only considered a medicine beneficial if it reduced pain by half. The medicines may have helped patients even when they didn’t reduce pain by that much.
Future research could use a different way to measure how well the medicines lower pain. Researchers could also account for differences in the cost of medicines.
How can people use the results?
Patients and doctors can use these results when considering how to treat pain in patients with CSPN.
Professional Abstract
Objective
To compare pain reduction, medication quit rates, and side effects among patients with cryptogenic sensory polyneuropathy (CSPN) taking one of four different pain medications
Study Design
| Design Element | Description |
|---|---|
| Design | Randomized controlled trial |
| Population | 402 adults age 30 and older diagnosed with CSPN who had baseline pain scores of at least 4 out of 10 |
| Interventions/ Comparators |
|
| Outcomes |
Primary: medication utility defined as a combination of 50% pain reduction and the percentage of patients who stopped taking the medication for any reason, side effects Secondary: pain interference with life and sleep, overall physical and mental health status, fatigue |
| Timeframe | 12-week follow-up for primary outcomes |
This adaptive randomized comparative effectiveness study compared the medication utility of four medications for treating CSPN pain: nortriptyline, duloxetine, pregabalin, and mexiletine. Researchers defined medication utility as a combination of efficacy in reducing pain by 50% from baseline and quit rate, which was the percentage of patients who stopped taking the medication for any reason.
The study included 402 patients with CSPN receiving care at one of 40 clinics. Of these, 85% were white, 7% were black, 4% were Asian, and 4% were from other or unknown races; 6% were Hispanic. The average age was 60, and 53% were male. All patients had a baseline pain score of at least 4 on a scale of 0 to 10 and had not taken any of the study medications for at least seven days before the baseline visit.
Researchers randomly assigned patients to take one of the four medications. Every three months, researchers analyzed medication performance and then used adaptive randomization so that more new enrollees received better performing medications. Patients completed surveys at baseline and 4, 8, and 12 weeks later.
Patients with CSPN, caregivers of patients with CSPN, and members of The Foundation for Peripheral Neuropathy helped design and implement the study.
Results
The medications with the highest utility scores were nortriptyline (utility = 0.81) and duloxetine (utility = 0.80), followed by pregabalin (utility = 0.69) and mexiletine (utility = 0.58). Possible utility scores range from 0–1.75, with higher scores indicating higher efficacy and lower quit rates.
- Of the patients taking nortriptyline, 25% reported efficacy, 38% quit taking the medication, and 56% reported side effects.
- Of the patients taking duloxetine, 23% reported efficacy, 37% quit taking the medication, and 47% reported side effects.
- Of the patients taking pregabalin, 15% reported efficacy, 43% quit taking the medication, and 40% reported side effects.
- Of the patients taking mexiletine, 20% reported efficacy, 58% quit taking the medication, and 39% reported side effects.
For patients who did not quit medication, mexiletine had the greatest reductions in scores for fatigue and pain interference with life. All four medications improved patients’ physical and mental health but didn’t change pain interference with sleep.
Limitations
Quit rates included patients who dropped out for any reason, including medication cost or lack of insurance coverage. Because pregabalin cost significantly more than the other medications, more patients stopped taking it for those reasons. Medications might have reduced pain without meeting the study’s defined pain reduction threshold of 50%.
Conclusions and Relevance
In this study, nortriptyline and duloxetine performed better than pregabalin and mexiletine. All four medications reduced pain for some patients.
Future Research Needs
Future research could include a crossover design if the initial assigned medication is nonefficacious. Studies could also use a different way to measure efficacy and account for differences in medication cost.
Final Research Report
View this project's final research report.
Journal Citations
Related Journal Citations
Peer-Review Summary
Peer review of PCORI-funded research helps make sure the report presents complete, balanced, and useful information about the research. It also assesses how the project addressed PCORI’s Methodology Standards. During peer review, experts read a draft report of the research and provide comments about the report. These experts may include a scientist focused on the research topic, a specialist in research methods, a patient or caregiver, and a healthcare professional. These reviewers cannot have conflicts of interest with the study.
The peer reviewers point out where the draft report may need revision. For example, they may suggest ways to improve descriptions of the conduct of the study or to clarify the connection between results and conclusions. Sometimes, awardees revise their draft reports twice or more to address all of the reviewers’ comments.
Peer reviewers commented, and the researchers made changes or provided responses. The comments and responses included the following:
- Reviewers raised questions about the structure and validity of the primary outcome of utility, a combination of efficacy and quit rate. One reviewer expressed concern that the measure had been biased because one of the medications tested had a much higher cost and therefore, higher quit rate that would affect it. The researchers noted that as a pragmatic trial, the study needed to include the available medication choices patients had. Other reviewers asked for a stronger rationale and explanation for how the researchers developed the utility function and what weighting they used. The researchers explained that they sought input from three clinical experts to determine the weighting between efficacy and quit rates, helping to establish the clinical meaning in the utility outcome.
- Reviewers suggested that a crossover design may have been better. The researchers agreed that in the future it could be helpful to use an adaptive crossover design where patients could be randomized a second time if they do not respond well to their initial treatment.
- Reviewers suggested that it would be useful to report patients’ prior experiences with the medications tested, or at least to note the medications they had used previously. The researchers said this information was not tracked, so they could not report on patients’ prior experiences with the tested medications.