Introduction

Pain is a multifaceted experience that can be triggered by a variety of painful stimuli. It is a response that involves a complex interplay between different components of the nervous system.1 The chronic nature of pain can drastically reduce one’s quality of life, which is why managing it has become a major focus. To address this, analgesic medications are designed to reduce the sensation of pain while allowing the individual to remain conscious. There are three main groups of analgesic medications2: opioids, non-opioids and drugs that are not initially classified as analgesics but have proven to have analgesic effects. Each group of these medications works through distinct pathways and carries its own benefits and drawbacks.

Opioids, such as oxycodone and morphine, bind to opioid receptors (mainly through the mu-1 receptor) to produce analgesic effects.3 Although they are potent agents, their main drawback is their high risk of addiction. Non-opioid analgesics are drugs that act on the body in a way that does not involve opioid receptors.4 Corticosteroids,5 6 non-steroidal anti-inflammatory drugs (NSAIDs),7 8 acetaminophen,9 cannabinoids10 and n-Methyl-D-aspartate (NMDA) antagonists11 12 are among the drugs in this category.

Non-opioids also have their own side effects. Some examples include gastrointestinal bleeding caused by using NSAIDs13 or liver damage caused by acetaminophen.14 15 Furthermore, they may not be effective in certain circumstances. Therefore, it is essential to continue to discover new drugs that can be used as analgesics, with the intention of obtaining the highest level of effectiveness while maintaining a high level of safety.

One specific group of medications that is also being used for their analgesic effects is antidepressants. Although antidepressants are not designed to have antinociceptive effects, they are being used as drugs to treat different types of pain.16–19 Among antidepressants, tricyclic antidepressants (TCA), which work by inhibiting norepinephrine and serotonin 5-hydroxytryptamine (5-HT) transmitters,20 21 are also proven to cause potent analgesic effects.22 23 They inhibit the reuptake of norepinephrine and serotonin by blocking their respective transporters, which increases the levels of these neurotransmitters in the synaptic cleft and enhances neurotransmission.24 Among all the TCAs, nortriptyline is considered one of the safest ones and has been reported to be an effective treatment for certain chronic pain conditions.25 Since some studies suggest that nortriptyline’s analgesic effects may be desirable and its side effects are relatively milder than those of other TCAs, it is important to review all the available data to draw a comprehensive and quantitative conclusion on its use in managing pain.

While some other reviews have pointed to the analgesic effects of nortriptyline, this study aims to gather all the existing data regarding this topic and give comprehensive insight. This study also aims to give quantitative data on nortriptyline’s analgesic effects, its safety and tolerability profile, the comparison of its efficacy in various types of pain and the efficacy of nortriptyline’s analgesic effect compared with other analgesics. Hence, the aim of this study is to respond to the following issue: in people with different types of pain, is nortriptyline effective in decreasing painful symptoms compared with placebo?

Methods

The research protocol of this study was registered in PROSPERO (CRD42023424533) and then followed. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses reference for systematic reviews26 and abstracts27 were also followed.

Search strategy

Two researchers carried out the search stage in February 2023. The following search phrases were used in Scopus, Web of Science and PubMed: ‘Nortriptyline’ AND ‘Pain’ OR ‘Analgesia’ OR ‘Analgesic’. All the syntaxes used for searching in each database are presented in online supplemental table 1. While there was a restriction for publication language and only English studies were included, there was no restriction for the publication date. Studies with titles or abstracts containing keywords were found and added to EndNote. The study team selected the final study after removing duplicates and finishing the screening processes.

Eligibility criteria and study selection

In this study, pain was the exposure of interest, and a comparison was made between the reduction in pain scores in the two arms. The intervention was defined as consuming nortriptyline. Duplicates were removed by two independent researchers, and the first screening stage was carried out according to the aims of the study. In the initial screening stage, studies focusing on side effects, reviews, investigations related to other TCAs, case reports and any irrelevant research were excluded. Through the second screening stage, clinical trials were included if nortriptyline was compared with placebo or other analgesics; data were reported as mean pain scores pretreatment and post-treatment; the type of pain was clear; the administration routine was clearly reported; no other intervention was considered, and results were reported properly. Following the second screening phase, the references were finalised after sharing the selected studies of each author and getting help from the principal investigator.

Data extraction

Data extraction was also carried out by two researchers. The extracted data were classified into three sections, which included:

Characteristics: authors and year, study location, sample size and the mean age of participants, type of pain and other comorbidities.

Data for systematic review: dose of nortriptyline and its administration routine, duration of trial, number of lost participants and their reasons; comparator arm and its administration routine; and the reported side effects.

Quantitative data for meta-analysis: the sample size, mean and SD of painful symptoms in both intervention and control groups, the outcome measure used in each study, percentage of males and mean dose of nortriptyline.

Both self-reported pain scores (ie, scales 1–10) and measured scores (ie, visual analogue scale, denote descriptor differential scales pain intensity and unpleasantness, and fibromyalgia impact questionnaire) and their changes from baseline to the end of the study were extracted. No score conversion was carried out. Painful symptoms refer to a feeling of discomfort experienced subjectively, encompassing physical, psychological and cultural aspects. This discomfort leads to incapacity and a decline in quality of life, consistently impacting the patient negatively.

Finally, tolerability rates were extracted as the proportion of participants who left the study because of any side effect.

Meta-analysis

A meta-analysis was performed to analyse the effect sizes of nortriptyline on lowering pain scores. When more than one publication provided their data as the means before and after therapy or as a comparison of nortriptyline with other analgesic drugs, the mean±SDs were pooled. The standardised mean difference (SMD) method was used because the outcome measurements varied throughout reference studies. However, in the case of pretreatment and post-treatment analysis, the standardised mean change (SMC) approach was used. Moreover, in the pretreatment and post-treatment analyses, negative SMC values show that the pain scores have reduced after the intervention. However, in the comparison of nortriptyline with placebo and other analgesics, positive SMD values show that nortriptyline was more effective, and negative values show that the comparator arm had more efficacy. A random-effect model was used since the intention was to generalise the results beyond the included studies. However, if the number of studies was less than five or the sample sizes of the included studies were heterogeneous, a fixed-effect model was considered. This approach is consistent with recommendations in the literature, where a fixed-effects model is often preferred in cases of a limited number of studies to avoid the potential overestimation of heterogeneity inherent in random-effects models.28 The heterogeneity both within and between subgroups was evaluated using the I2 (%). Both meta-regression and subgroup analysis were carried out in cases of observed heterogeneity to provide complementary information. Subgroups were categorised by mean age, type of pain, trial duration and gender. Since several studies used flexible dosing, it was impossible to perform a subgroup analysis by medication mean dose. Meta-regression was used to explore the relationship between study-level covariates and the effect sizes. Furthermore, it allowed us to investigate how continuous and categorical moderator variables influence the overall effect size. Subgroup analyses, on the other hand, were conducted to compare effect sizes across predefined categorical groups. This approach helps identify whether the effect size differs significantly between distinct groups. To measure publication bias, Egger’s test was used. A two-sided p value of less than 0.05 was considered statistically significant. For all statistical studies, STATA V.17 was used.

Risk of bias and certainty assessment

The Cochrane Collaboration method was applied to evaluate the final included studies' risk of bias.29 This process was carried out by two independent reviewers. Finally, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria30 were used to assess each outcome’s certainty.

Patient and public involvement

No patient was involved.

ResultsStudy selection

A flowchart depicting the screening stages is displayed in figure 1. Using the mentioned search protocol, a total of 648 articles were initially retrieved, comprising 217 from Web of Science, 235 from Scopus and 196 from PubMed. 351 studies were sent to the initial screening stage after 297 duplicates were eliminated. The criteria listed in the methodology section led to the final exclusion of 332 publications from the first step’s title and abstract screening. Five studies were eliminated after a full-text assessment of the remaining 19 papers. Among the five studies excluded, four started with nortriptyline, but they switched to another TCA during the trial. The last paper was excluded because the effect of nortriptyline on the efficacy of morphine was reported. Data from 14 studies were eventually incorporated into the review after meeting all inclusion criteria.31–44

Figure 1

The flow diagram of the study selection process for evaluating the efficacy of nortriptyline in reducing pain. TCA, tricyclic antidepressants

Basic characteristics of the selected studies

The key characteristics of the final 14 included studies are summarised in table 1. Out of 14 articles, four were carried out in the USA,32 33 37 41 two were carried out in Iran,38 43 two took place in Canada,36 42 two were done in Poland,40 44 and one article was conducted each in Brazil, the UK, India and New Zealand.31 34 35 39 Concerning the study date, approximately half of the studies were conducted post-2010, while the remaining studies were comparatively older. Sample sizes exhibited variability across studies, ranging from 14 to 228 participants. Participants’ mean age varied between 25.6 and 64.5 in different studies. In terms of the individuals’ health, some of the participants in some references had diabetes, major depressive disorder (MDD), dry eye, glaucoma and postherpetic keratitis, while other participants in other trials had no medical comorbidities at all.

Table 1

The main characteristics of the included studies

Qualitative analysis

The findings of the research examining the impact of nortriptyline use on pain management are provided in table 2. Nortriptyline was used with different doses (12.5–150 mg daily) and was administered for various types of pain. While all the other studies reported that nortriptyline significantly reduces pain, one study reported its ineffectiveness. This little inconsistency may be due to the different types of studied pains. For example, although nortriptyline was reported to significantly reduce pain severity in chronic low back pain32 and painful neuropathy38 compared with placebo, the results of one study reported that it was not superior to placebo in fibromyalgia.31 Nortriptyline was further reported to significantly reduce painful symptoms in major depressive disorder,40 chronic pelvic pain37 and neuropathic corneal pain.41 It was also reported that while nortriptyline is beneficial in reducing knee osteoarthritis pain, it is not superior to placebo since their difference did not reach statistical significance (p=0.06).34 Furthermore, some studies compared nortriptyline’s efficacy with other analgesics; it was reported that nortriptyline can be as efficacious as amitriptyline in controlling peripheral neuropathic pain42 and postherpetic neuralgia (PHN).35 While one study reports that nortriptyline was superior to gabapentin in chronic orchialgia,39 another study reported its efficacy did not significantly differ from gabapentin in PHN.35 It is worth mentioning that one study33 reported that nortriptyline alone was better than morphine or a combination of morphine and nortriptyline in chronic lumbar root pain. While comparing nortriptyline with serotonin-norepinephrine reuptake inhibitors, one study reported that nortriptyline was equally effective as venlafaxine44 in painful symptoms of major depressive disorder, and another study reported that while nortriptyline’s efficacy was significant, it was lower than duloxetine in diabetic peripheral neuropathic pain.43 Finally, another study on painful symptoms in MDD reported that nortriptyline was equal in efficacy to escitalopram.44

Table 2

Summary result of clinical trials assessing the efficacy of nortriptyline in controlling pain

Regarding safety, the most common adverse events were xerostomia and constipation. Insomnia and sleepiness were also reported. Only one study35 reported cardiovascular side effects. Although six studies reported a desirable tolerability rate (<10%), one study reported 35% tolerability.41 Studies comparing various analgesics reported that while nortriptyline’s tolerability is better than amitriptyline, gabapentin surpasses nortriptyline in terms of safety and tolerability.

Quantitative synthesis

The summary results of all the meta-analyses are reported in table 3. Analyses were presented in three areas, as can be seen: data comparisons as pretreatment and post-treatment, comparisons with placebo and comparisons with different alternative analgesics.

Table 3

Meta-analysis results of reducing pain by nortriptyline

The pooled SMCs of nortriptyline’s analgesic effect as a comparison of pretreatment and post-treatment are reported in figure 2. The overall pain score significantly decreases by consuming nortriptyline (−1.20, 95% CI (−1.48 to –0.93); p<0.001; I2: 56.67%; p<0.05). Meta-regression and subgroup analysis were used to identify the cause of heterogeneity. The percentage of men, mean age, length of the study and kind of pain were selected as moderators in order to perform meta-regression. No chosen moderator was found to be the source of heterogeneity (online supplemental table 2). Additionally, a subgroup analysis was carried out. The results revealed no statistically significant variations in any of the groupings, including pain types (online supplemental table 3). Publication bias did not exist (coefficient: 3.04; p=0.22).

Figure 2

The pooled data on the efficacy of nortriptyline in reducing pain (compared with pretreatment and post-treatment).

The pooled SMDs for nortriptyline’s analgesic effect (compared with placebo) are shown in figure 3. As can be seen, nortriptyline significantly reduces pain compared with placebo (0.43, 95% CI (0.23 to 0.64); p<0.001; I2: 53.13%; p=0.09). Given that the heterogeneity was not significant, subgroup analysis and meta-regression were not performed. There was evidence of publication bias in the studies (coefficient: 3.25; p<0.05). All the results obtained from the leave-one-out analysis were within the 95% CI of the primary result. Therefore, the sensitivity analysis revealed no differences in the outcomes.

Figure 3

The pooled data on the efficacy of nortriptyline in reducing pain (compared with placebo).

The pooled SMDs for the comparison of nortriptyline with other alternative analgesics (amitriptyline, duloxetine, venlafaxine and gabapentin) in reducing pain are shown in figure 4. As can be seen, the efficacy of nortriptyline in reducing pain compared with other drugs does not reach statistical significance (−0.18, 95% CI (−0.39 to 0.03); p=0.08; I2: 74%; p<0.01). Meta-regression and subgroup analysis were used to identify the cause of heterogeneity. The trial duration, mean age and proportion of men were selected as moderators in order to perform the meta-regression. It was revealed that trial duration is one of the moderators causing heterogeneity (online supplemental table 2). Therefore, a subgroup analysis was carried out to show how the duration of the trial affects the outcomes. The results of subgroup analysis showed that mean age and trial duration are sources of heterogeneity (online supplemental table 3). It was revealed that nortriptyline has a better analgesic effect on people older than 50 years old (compared with people less than 50 years old), and it was also shown that trial durations less than 7 weeks have better outcomes compared with trial durations that were more than 7 weeks. There was no evidence of publication bias among the studies (coefficient: 3.11; p=0.22).

Figure 4

The pooled data on the efficacy of nortriptyline in reducing pain (compared with other analgesics).

Outcomes certainty

The results of the GRADE criteria are reported in table 4. As can be seen, there are four main outcomes reported by this study. The first outcome is the efficacy of nortriptyline as an analgesic, which had a high certainty. Equality of effectiveness of nortriptyline with amitriptyline and gabapentin got a low and moderate certainty score, respectively. Finally, it was shown that the certainty about the tolerability of nortriptyline as an analgesic was high. Finally, figure 5 illustrates the results of assessing the risk of bias among the reference studies.

Figure 5

The result of the Cochrane Collaboration’s tool for assessing the risk of bias in the included studies.

Table 4

Grading of Recommendations Assessment, Development and Evaluation evidence profile, using nortriptyline as an analgesic agent

Discussion

This study reported the efficacy and safety of nortriptyline as an analgesic agent. The advantage of this study over other studies is its quantitative reports, as well as comparing the efficacy of nortriptyline in various types of pain. Moreover, comparative data on the analgesic effect of nortriptyline was reported. This evaluation showed that nortriptyline is an effective medication for reducing pain. Its effectiveness and tolerability as an analgesic agent were strongly evidenced. Moreover, there are some studies showing that it can be as good as amitriptyline and gabapentin in reducing pain.

Furthermore, our analysis showed that nortriptyline’s analgesic effects (when compared with other analgesics) are stronger in people >50 years old. Nortriptyline’s stronger analgesic effects in people over 50 years old compared with other analgesics might be due to several factors. Older adults may have different pain perceptions and drug metabolisms, making them more responsive to nortriptyline. They might also experience benefits from its antidepressant effects and improved sleep due to its sedative properties. Additionally, older individuals might have developed tolerance or adverse reactions to other analgesics, making nortriptyline more effective for them.

Moreover, there was evidence that nortriptyline may show better analgesic effects in trial durations of less than 7 weeks compared with longer durations and that can be due to several factors. Initially, patients may experience a stronger response, including a placebo effect, which can diminish over time. Tolerance to the medication can develop, reducing its effectiveness with prolonged use. Cumulative side effects may negatively impact pain relief and adherence. The natural course of chronic pain conditions can also lead to variations in pain levels, independent of the medication. Additionally, patient adherence might decline in longer trials due to side effects or a perceived lack of effectiveness. Finally, shorter trials often benefit from heightened patient expectations and more rigorous monitoring, enhancing perceived effectiveness.

Nortriptyline is a TCA that is United States Food and Drug Administration-approved for the treatment of depression. As reported by other studies, antidepressants that inhibit norepinephrine and 5-HT transmitters (including nortriptyline) have a more potent analgesic effect.16–19 45 They are effective analgesics due to their ability to block the reuptake of both norepinephrine and serotonin, which enhances pain modulation pathways in the central nervous system. Additionally, their strong antihistamine effects may contribute to pain relief by reducing local inflammation and promoting sedation, which can help patients cope better with chronic pain.46 Although nortriptyline also has anticholinergic effects,47–49 it is reported to have fewer side effects than other TCAs.50 51 The most frequently reported side effects of nortriptyline were xerostomia, dizziness, nausea, constipation, lethargy and insomnia. The less frequently reported ones were sedation, drowsiness, headache, abdominal pain, urine retention and weight gain.

Nortriptyline is believed to reduce pain through its effects on multiple neurotransmitters. It is thought to act on the monoamine neurotransmitters, such as norepinephrine and serotonin, by inhibiting their reuptake and increasing their availability in the synaptic cleft.52 53 This increased availability is thought to reduce pain by modulating pain signals and decreasing their transmission.54 55 Nortriptyline has also been found to interact with other molecules in the body, such as GABA A receptors, to modulate neurotransmission.56 57 Additionally, nortriptyline has been found to induce analgesic effects by decreasing the levels of proinflammatory cytokines in the body, thereby reducing inflammation.58 All these effects of nortriptyline may contribute to its efficacy in reducing pain.

Regarding other probable mechanisms that are hypothesised for the analgesic effects of nortriptyline, studies have made some arguments. Nortriptyline’s analgesic efficacy as a TCA seems to arise from its action on descending modulatory inhibitory controls and the effect caused by this medicine on the locus coeruleus and the spinal cord.59 60 Moreover, it is reported that nortriptyline has sodium and calcium channel blockade activity.61 This sodium blockade effect of nortriptyline might also be conducive to its analgesic development along with NMDA blockade.62

Nortriptyline also has a beneficial mechanism of action on the 5-HT and noradrenergic (NA) systems by inhibiting the reuptake of serotonin and norepinephrine transmitters.21 40 63 NA reuptake inhibition intensifies analgesic effects through two main mechanisms. First, inhibiting norepinephrine reuptake leads to analgesic development through α2-adrenergic receptors in the dorsal horn of the spinal cord.64 65 Activation of α2-adrenergic receptors leads to effective antinociceptive activity.66–68 For the second mechanism, NA affects the NA inhibitory system of the locus coeruleus and enhances its function.64 69 70

In line with our study, other publications also report the use of TCAs to lower painful symptoms. For example, Bryson and Wilde71 carried out a review study on the efficacy of amitriptyline in controlling pain. Different types of chronic pain, such as PHN, painful diabetic neuropathy, central poststroke pain, fibromyalgia, rheumatoid arthritis, non-malignant chronic pain, trigeminal neuralgia and cancer pain, were assessed. According to this review, amitriptyline effectively controlled the pain and significantly reduced the painful symptoms of PHN, achieving a good to excellent response in two-thirds of patients with a reduction of intensity of 21%–46%. Furthermore, for diabetic neuropathy, amitriptyline caused moderate to good pain relief in three-quarters of patients.

Despite nortriptyline, which was proven to be ineffective in fibromyalgia, amitriptyline was proven to be effective for fibromyalgia or those with related or unrelated chronic pain from malignancy. The review’s outcome showed that amitriptyline was inadequate for rheumatoid arthritis pain. Still, despite the lack of evidence, amitriptyline has been widely used and recommended for uncontrolled cancer pain alongside other analgesic compounds. The most frequent side effects reported were dry mouth and sedation, constipation, nausea and urinary retention. By comparing the results of the amitriptyline study with our study and by revealing the effectiveness of nortriptyline in some types of pain, such as PHN, painful diabetic neuropathy and fibromyalgia, it can be concluded that nortriptyline can cause a significant reduction in pain score while being better tolerated and safer for patients suffering from pain. However, since the efficacy of amitriptyline, in addition to its side effects, may be greater, an expert clinician should decide whether nortriptyline or amitriptyline should be chosen for each patient.

In another study, Hearn et al72,72 reviewed desipramine’s efficacy in controlling neuropathic pain. Desipramine is another member of the TCA family, and the usual dosage of desipramine that might be used for treating neuropathic pain starts at 10 mg daily and will be increased up to 150 mg daily if necessary. This review studied two main types of pain: painful diabetic neuropathy and PHN. The results of a total of 130 participants who took desipramine were gathered and reported. When compared with a placebo, all studies showed some benefit with desipramine (often at a dose of 100–150 mg daily). The primary concern was that each of them contained one or more potential major bias factors that could cause the effectiveness of desipramine to be overestimated. The common adverse effects of desipramine include xerostomia, constipation and weight gain. Comparing the results of desipramine with nortriptyline, it can be concluded that, with options like nortriptyline and amitriptyline, desipramine may not be the drug of choice for reducing painful symptoms. It seems that nortriptyline is more effective than desipramine, in addition to having fewer side effects.

In the case of other antidepressant groups, studies have shown that they can also be beneficial in controlling pain. For instance, venlafaxine is a serotonin-norepinephrine reuptake inhibitor and might have analgesic effects through the same pathways. Grothe et al73 reviewed venlafaxine’s efficacy in treating pain syndromes. The different types of pain that were assessed were chronic pain associated with MDD, painful physical symptoms of generalised anxiety disorder (GAD), headache (migraine and chronic tension-type headache), fibromyalgia, postmastectomy pain syndrome and neuropathic pain. According to this review, although additional large-scale trials are required, venlafaxine may be efficacious in reducing pain in patients with both depression and chronic pain. Results of the reviewed studies indicated that venlafaxine is also an effective treatment for painful physical symptoms of GAD, migraine and chronic tension-type headaches. It is worth saying that for fibromyalgia, only one clinical trial with the aim of evaluating the effect of venlafaxine has been carried out, and the reports of 6 out of 11 participants (who completed the study) show a 50% or higher decrease in pain.

Overall, nortriptyline can be an effective treatment option for those struggling with depression or chronic pain. Still, it should always be used under the guidance of a healthcare professional to ensure safety and effectiveness. Finally, future studies will be established on assessing the effect of nortriptyline in chronic pain associated with MDD, painful physical symptoms of GAD, headache (migraine with or without aura and coexisting migraine and chronic tension-type headache), postmastectomy pain syndrome, neuropathic pain after treatment of breast cancer and painful polyneuropathy would be a substantial step forward in evaluating different aspects of nortriptyline’s antinociceptive effect.

Strengths and limitations

This study is one of the first meta-analyses to thoroughly gather data about the efficacy of another TCA (rather than amitriptyline) in reducing pain. Its strength lies in its comprehensiveness in reporting the results; all the existing data on efficacy, safety and tolerability were reported as much as data existed. Moreover, all the possible conclusions were made and reported (the GRADE table). Although some of the findings had low certainty, they are useful for showing future scientists in which areas we need more trials for a reliable conclusion. This study also has some limitations. First, since the reference studies used several doses, it was impossible to draw a unique conclusion about the optimum dose of nortriptyline for reducing pain. Second, the number of reference studies was very low in some of the meta-analyses. Finally, due to the lack of data, it was impossible to compare nortriptyline with each group of alternative analgesics separately, and all the alternative analgesics from various groups were accumulated in one arm of comparison.

Conclusion

While nortriptyline is effective in some chronic pains, such as neuropathies, it lacks efficacy in some other chronic pains, such as fibromyalgia and osteoarthritis. Nortriptyline is well tolerated when administered in doses intended for its analgesic effects. Moreover, several studies suggested that the analgesic effects of nortriptyline are comparable to those of amitriptyline and gabapentin.