Summary
In people with knee OA, adding nortriptyline to their usual analgesic treatment did not meaningfully improve pain, function, stiffness, or each participant’s global assessment of OA. Participants randomised to nortriptyline were more likely to have days when they did not take paracetamol or NSAIDs and, when they did take NSAIDs, they took fewer doses; however, these differences in analgesic use were small and unlikely to be clinically important. Dry mouth, constipation, sweating, and sexual dysfunction were more likely in participants taking nortriptyline, though sexual dysfunction was not statistically significant. Serious adverse events occurred in four participants taking nortriptyline and three taking placebo.
Of the SAEs, two were judged to be related to study medication and one was life-threatening (all of these occurred in participants taking nortriptlyine).
Strengths and limitations
To the authors’ knowledge, this is the first published, double-blind randomised controlled trial of the analgesic effect of a TCA on OA. In addition, there are a number of strengths to the study design: primary and secondary outcome measures were recorded at 14 weeks, a follow-up period that is consistent with OMERACT-OARSI OA study recommendations;37 the primary outcome was measured using the WOMAC pain subscale, a valid, reliable, and responsive measure of pain and disability in OA;38–39 and the study was adequately powered to detect the minimum clinically important difference in pain. However, although this study was adequately powered to detect a clinically important effect of nortriptyline on pain, the sample size was too small to allow for subgroup analyses of participants who may have been predisposed to derive greater benefit from nortriptyline — for example, those with low mood or higher baseline levels of pain.
The pragmatic study design, in which study medication was taken in addition to usual treatment, is considered a strength: as a result of this, the effect of nortriptyline was tested in the context in which it would be used in clinical practice. However, as the design placed no limitation on participants’ use of other analgesics, it is possible that an analgesic effect of nortriptyline may have been masked that would have, otherwise, been apparent had the use of other analgesics been restricted.
Study participants were recruited from a number of sources. The majority were those with knee OA who had been declined assessment for knee replacement and returned to their GP’s care; others were recruited through a range of community-based advertising approaches. Participant demographics were broadly representative of patients with OA, though people of non-European ethnicity were under-represented. The recruitment of individuals referred for, and declined, specialist assessment may have meant that the range of disease severity in participants was greater than is typically encountered in primary care; it is important to be aware, therefore, that this may limit extrapolation of the findings to the full range of patients with knee OA that is encountered in primary care.
The study design also required participants’ study medication doses to be individually titrated according to their levels of pain and adverse effects believed by the participant to have been caused by study medication. This is important as nortriptyline metabolism and, hence, dosing have high inter-individual variability: the effective and tolerated daily dose ranges from <25 mg to >100 mg, so individualised dosing is essential.40–41 The choice of a dosing range from 25 mg to 100 mg daily could have been a limitation in that some participants may have received subtherapeutic dosing even at the maximum study dose, while others may have developed intolerable adverse effects at the minimum dose and ceased study medication as a result. However, the study dosing range was consistent with current clinical recommendations40 and was a pragmatic approach to permit flexible individualised dosing in the limited time available in the study. Furthermore, this process of dose adjustment closely resembles usual clinical practice when initiating a TCA.
The authors were able to demonstrate reasonably effective blinding of participants. This is of particular importance in trials of TCAs, as these medicines have a well-recognised set of adverse effects (in particular, dry mouth, constipation, and sedation) that may lead to unblinding, which could have compromised the internal validity of the study.
Participants’ baseline characteristics were generally similar in the placebo and nortriptyline arms. The nortriptyline arm, however, included a greater proportion of individuals who were obese. Individuals with a higher BMI report greater OA pain than those with lower BMI;42 therefore, the greater proportion of obese individuals in the nortriptyline arm may have biased results towards the null. However, mean BMI and the proportion of individuals with healthy BMI were similar in the two study arms, and the nortriptyline arm included a smaller proportion of those classified as overweight, so any effect on the findings is likely to have been small.
This may have introduced bias to the findings, although the mean BMI was similar in the two study arms, and adjusting for BMI and other key baseline variables did not substantially alter them.
Comparison with existing literature
To the authors’ knowledge, this is the first trial of a TCA for pain in OA; therefore, no directly comparable studies exist. The null finding is disappointing as achieving adequate, well-tolerated, and safe analgesia for patients with OA is challenging, and few trials of analgesic agents demonstrate an effect size equal to the minimum clinically important difference.11,19,33
The evidence of TCAs’ efficacy in other chronic pain conditions is mixed: TCAs are established as first-line agents in neuropathic pain43 and have been shown to be effective in chronic headache,22 post-herpetic neuralgia, and diabetic neuropathy.21 Their efficacy in fibromyalgia is less clear,44–45 and a recent RCT of amitriptyline in chronic back pain did not show a statistically significant improvement in pain.46 In OA, the relative contribution of central and peripheral sensitisation and nociceptive pain varies between individuals;47 this may mean that some people are more likely to benefit from centrally acting analgesics than others.
