Tricyclic Antidepressants in Nociceptive and Neuropathic Pain: A Review of Their Analgesic Properties in Combination With Opioids

Abstract

Objectives: To determine the efficacy and safety of commonly prescribed tricyclic antidepressants (TCAs) as analgesics for nociceptive and neuropathic pain in combination with opioids. Data Sources: A comprehensive literature review was conducted with the assistance of a medical reference librarian on PubMed, MEDLINE, Scopus, and Web of Science using the following search terminology: “Amitriptyline” OR “Doxepin” OR “Desipramine” OR “Imipramine” OR “Nortriptyline” OR “Clomipramine” OR “Trimipramine” AND “Analgesia.” Reports of adult patients who received any TCA as an adjunctive analgesic to opioids were included. Study Selection and Data Extraction: A total of 293 results were obtained from the initial database inquiries, following which exclusion criteria were applied and 6 articles were included in this review. Three of the reports detailed the use of TCAs in the perioperative setting, whereas the remaining 3 evaluated their effect on different etiologies of neuropathic pain. Data Synthesis: Tricyclic antidepressants were found to have modest, yet not insignificant, independent analgesic properties, although the ability to provide pain relief was relegated to a select few agents. Desipramine has the most data available for use in nociceptive, postoperative pain through its ability to potentiate and prolong the analgesic effects of opioids and was not associated with adverse drug effects. Conclusions: The efficacy of TCAs for neuropathic pain was not corroborated by this review, and the anticholinergic adverse effects associated with this drug class were found to be significant. Further research is needed to quantify the efficacy of TCAs in the management of nociceptive pain.

Introduction

Despite the relative decrease in opioid prescriptions furnished and filled, in conjunction with a general decline in both illicit and synthetic opioid-related deaths, opioid abuse and deaths associated with opioid misuse have slightly risen over the past 6 months.^1,2 Opioids remain the most efficacious and widely studied analgesics, and are an integral part of pain relief regimens, even with their known addictive properties and adverse effect profiles.^3,4 Multimodal pain management strategies are being employed in the perioperative, inpatient, and outpatient settings, but opioids continue to serve as the backbone of most medication combinations. Adjunctive agents have the ability to provide improved analgesia and decrease the amount of opioids necessary to achieve pain relief, making them an attractive option for clinicians.^3,4

Tricyclic antidepressants (TCAs) have been on the market for decades and have a plethora of indications, including the management of depressive and mood disorders, alcohol withdrawal symptoms, and generalized anxiety.^5,6 The medications in this class include amitriptyline, clomipramine, desipramine, doxepin, imipramine, nortriptyline, and trimipramine.^5,6 While their primary mechanism of action is to modulate norepinephrine and serotonin levels, they have also been found to affect histamine receptors, muscarinic receptors, and peripheral alpha₁-adrenergic receptors, leading to the class being associated with sedation, drowsiness, and orthostasis.^{5 -7} It is important to note that while some clinicians consider sedation a negative adverse effect, a comparative analysis conducted by Hummel et al ⁸ described the sedating nature of these agents as a positive contributor to their efficacy as analgesics.

Tricyclic antidepressants can be further divided into 2 specific categories of drugs based on their chemical structure and function: those that are secondary amines and primarily mediate norepinephrine, and those that are tertiary amines and mediate both norepinephrine and serotonin. ⁵ A list of commonly prescribed agents and their respective subclasses can be viewed in Table 1.

Table 1.

Structure of Tricyclic Antidepressants.^{5 -7}.

Medication	Chemical structure
Nortriptyline a	Secondary amine
Trimipramine	Secondary amine
Desipramine b	Secondary amine
Amitriptyline	Tertiary amine
Doxepin	Tertiary amine
Imipramine	Tertiary amine
Clomipramine	Tertiary amine

^aNortriptyline is an active metabolite of amitriptyline.

^bDesipramine is an active metabolite of imipramine.

The objective of this review was to determine the efficacy and safety of commonly prescribed TCAs as analgesics for nociceptive and neuropathic pain in combination with opioids.

Methods and Materials

A systematic literature review was conducted, in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, on PubMed, MEDLINE, Scopus, and Web of Science using the following search terminology: “Amitriptyline” OR “Doxepin” OR “Desipramine” OR “Imipramine” OR “Nortriptyline” OR “Clomipramine” OR “Trimipramine” AND “Analgesia.” Two of the authors contributed to the literature evaluation and retrieval process, while all 3 were involved in data extraction and synthesis. Reports detailing adult patients who received a TCA as an adjunctive analgesic to opioids with complete efficacy and safety outcome measures were included in this review. Reports detailing pediatric and pregnant patients, those conducted in a subject medium other than humans, those using TCAs for an alternative indication other than analgesia, those without outcome data, and those not readily available in English were excluded. Data filters were applied during database inquiries. All primary literature was considered in this review if inclusion criteria were met. A schematic of search methodology can be found in Figure 1.

Figure 1.

Search methodology.

Results

A total of 293 results were obtained following the initial database inquiry. Following the removal of duplicates and the application of exclusion criteria, 6 reports were ultimately included in this review. Three of the reports included detailed the use of a TCA in the perioperative setting, with drugs being administered prior to or immediately following a surgical procedure in an effort to decrease both pain scores and opioid doses consumed. Of those 3 trials, 2 were conducted in dental procedures, whereas the other was conducted following total hip arthroplasty. The remaining 3 trials described the use of a TCA in the management of neuropathic pain, including neuropathies associated with malignancy, postherpetic neuralgia, and chronic neuropathic pain. A summary of included trials can be found in Table 2.

Table 2.

Results.

Author	Study design and intervention	Indication	Medication regimens	Outcomes	Notable ADE’s	Clinical considerations
Levine et al 9	RCT: number of patients not disclosed Interventions: AMI + MOR DES + MOR Placebo +MOR	Dental surgery	AMI = 25 mg po daily for 7 days DES = 25 mg po daily for 7 days MOR = dosed per physician following surgery	DES was found to potentiate and prolong the analgesic effects of MOR	None reported	The magnitude of analgesia produced by the combo DES and MOR was significantly larger than that produced by the combination of either placebo or AMI with MOR
Gordon et al 10	RCT: 60 patients Interventions: Three different regimens of DES	Dental surgery	DES = 50 mg po qHS × 7 days DES = 50 mg po qHS × 3 days after surgery DES = 50 mg PO qHS × 3 days starting 7 days before surgery MOR = 6 mg IV postoperatively	DES administered 3 days prior to surgery was as efficacious as when it was administered 7 days prior to surgery	None reported	Corroborates evidence provided from Levine trial
Kerrick et al 11	RCT: 28 patients Interventions: AMI Placebo	Total hip or knee arthroplasty	AMI = 50 mg po daily for 3 days postoperatively vs placebo + MOR = 0.3 mg/mL PCA or MEP 3 mg/mL PCA	AMI cohort associated with a greater degree of pain on days 1-2 postoperatively	AMI was associated with an increased amount of sleep	Sleepiness has been associated with improved analgesic response to opioids in other trials, although this was not concluded by this RCT.
Mercadante et al 12	RCT: 16 patients Interventions: AMI Placebo	Pain in advanced cancer	AMI = 25 mg po × 3 days followed by 50 mg po × 4 days vs placebo + MOR at home dose	No significant changes in pain presence or severity noted	AMI associated with higher incidence of anticholinergic side effects, specifically drowsiness and dry mouth
Banerjee et al 13	RCT: 88 patients Interventions: AMI GABA	Neuropathic pain in malignancy	AMI = 25-100 mg PO daily + TRAM = 150-200 mg po daily vs GABA = 600-1800 mg po daily + TRAM = 150-200 mg po daily for up to 6 months	Both AMI and GABA resulted in improved pain scores on the VAS, though neither reached statistical significance.	Though not statistically significant, patients in the AMI cohort were more likely to develop anticholinergic ADEs, including dry mouth and dizziness	Patients in the AMI cohort were more likely to require rescue analgesics with either oral morphine or transdermal fentanyl patches
Rowbotham et al 14	RCT: 47 patients Interventions; AMI DES FLU	Postherpetic neuralgia	DES = titrated to a max of 150 mg po daily AMI = titrated to a max of 150 mg po daily FLU = titrated to a max of 60 mg po daily 11/47 patients concomitantly took home opioid doses	DES produced the greatest reduction in pain intensity (47%), followed by AMI (38%), and fluoxetine (35%).	Two patients dropped out of the study from the DES and AMI groups due to sedation and symptomatic orthostasis, respectively	The 11 patients using opioids at the start of trial had smaller reductions in pain compared with those not using concomitant opioids, thereby demonstrating that both DES and AMI have moderate yet present analgesic properties.

Abbreviations: ADEs, adverse drug events; AMI, amitriptyline; DES, desipramine; FLU, fluoxetine; GABA, gabapentin; IV, intravenous; MEP, meperidine; MOR, morphine; PCA, patient-controlled analgesia; po, orally; RCT, randomized controlled trial; TCA, tricyclic antidepressant; TRAM, tramadol; VAS, Visual Analog Scale; qHS, at bedtime.

A randomized controlled trial (RCT) conducted by Levine et al ⁹ administered amitriptyline 25 mg by mouth daily, desipramine 25 mg by mouth daily, or a placebo for 1 week prior to surgery, followed by a single postoperative dose of morphine in patients undergoing dental operations. Patients’ pain scores were calculated on the Visual Analog Scale (VAS), with assessments being made every 20 minutes postoperatively up to 150 minutes. While neither of the TCAs demonstrated independent analgesic properties, desipramine was found to increase the efficacy and prolong the duration of the analgesia provided by morphine as evidenced by the authors’ statistical analysis of the magnitude of analgesic responses at the 150-minute pain assessment. This finding was further corroborated by Gordon et al, ¹⁰ who conducted a prospective observational study in 60 patients evaluating the timing of desipramine administration regarding opioid analgesic potentiation. Rather than administering the drug for 7 days as with the Levine trial, Gordon et al concluded that 3 days was sufficient to achieve the desired effects from desipramine on morphine efficacy and duration. A similar statistical analysis of patients quantified the potentiation of morphine by desipramine by evaluating the magnitude of analgesia at 160 minutes post-dose.^9,10

The final included study evaluating the perioperative setting was performed by Kerrick et al, ¹¹ whose RCT was conducted in 28 patients undergoing total hip or knee arthroplasty. Patients received either 50 mg of oral amitriptyline or placebo, in combination with a morphine or meperidine patient-controlled analgesia (PCA) device, for 3 days postoperatively. ¹¹ Pain scores, as measured on the VAS, were higher in the amitriptyline cohort, indicating a greater degree of pain; however, amitriptyline was found to help with sleep as opposed to placebo. Kerrick et al ¹¹ concluded that amitriptyline, at the studied dose and frequency, was an unnecessary but unharmful adjunctive agent.

In an effort to determine the efficacy of amitriptyline as an adjunctive analgesic in conjunction with morphine in advanced cancer patients, Mercadante et al ¹² conducted an RCT in 16 patients who received 25 mg of oral amitriptyline nightly for 3 days followed by 50 mg nightly for 4 days in comparison with placebo. Dosing considerations were made for geriatric patients who required an adjusted regimen. No significant differences were noted between cohorts, although the amitriptyline group was associated with a higher degree of anticholinergic adverse effects, including drowsiness and dry mouth. ¹² A quality of life assessment also failed to determine a difference between cohorts. ¹² Similar questionable utility of amitriptyline in cancer patients was determined by Banerjee et al, ¹³ whose RCT compared either amitriptyline or gabapentin with tramadol in patients with malignant disease. Eighty-eight patients between the ages of 18 and 70 years were randomized into 2 cohorts and had their pain scores evaluated on the VAS. A nonstatistically significant decrease in the VAS was observed in both cohorts, although numerically more patients in the amitriptyline cohort required rescue analgesics and experienced significant adverse effects, all of which were anticholinergic in nature. ¹³

In a 3-arm RCT, Rowbotham et al ¹⁴ sought to determine the efficacy of antidepressants for the management of postherpetic neuraglia. Thirty-eight patients completed the 3-week evaluation, 11 of whom were receiving concomitant opioid therapy which was continued from outpatient use. Patients were titrated to receive daily doses of either 150 mg oral desipramine or amitriptyline or 60 mg oral fluoxetine. Both the TCAs were more effective in reducing pain than fluoxetine, with desipramine being associated with the greatest reduction in pain intensity, although none of the results reached statistical significance. No significant differences in pain reduction were appreciated in the patients receiving opioids than those not receiving opioids. Fluoxetine was reported to have the highest degree of nonadherence, with 1 patient being hospitalized for clinically significant hyponatremia attributed to the drug. ¹⁴

Discussion

Despite the relatively underwhelming evidence discovered as a result of this review, several important pieces of information can be taken from the clinical trials discussed and subsequently applied to patient care at the bedside and in the outpatient setting. Select TCAs may be reasonable adjunctive analgesics to opioids in select patient populations, such as those evaluated in the included studies of this review, however; it is equally important to recognize which medications did not demonstrate efficacy and had safety concerns. With the exception of increasing sedation and sleep in patients, amitriptyline was found to be an ineffective adjunctive analgesic in all trials evaluated in this review.^{11 -14}

While the information in this review does not support the notion of all TCAs having utility as adjunctive analgesics, desipramine is of particular interest for this indication. This claim is supported by the outcomes of the Levine, Gordon, and Rowbotham trials discussed previously, however; the results of the Levine and Gordon studies pose a significant quandary, in that they demonstrate the ability of desipramine to potentiate and prolong the analgesic effects of an opioid for nociceptive pain.^9,10,14 The classification of pain is a subtle yet important distinction, as most medications used as adjunctive analgesics that mediate norepinephrine or serotonin are typically relegated to use in neuropathic pain. ¹⁵

Perhaps the most concerning finding of this review were the significant adverse drug effects associated with the TCAs.^{11 -13} Despite using relatively low doses of amitriptyline and other TCAs in some of the clinical trials reviewed, patients were still plagued by the notorious anticholinergic adverse effects of the TCA drug class.^{11 -13} Sedation, drowsiness, and dry mouth were the most reported effects in this review; others, including impaired lacrimation, urination, and defecation, are also associated with this class of drugs but were not specifically reported in the trials reviewed in this work.^6,7 Careful monitoring, especially in geriatric patients or other populations at an increased risk of developing these adverse effects, is warranted. In addition, patients who have a history of suicidal ideation or actions, or those with an unstable mental illness, should be carefully evaluated before being prescribed a TCA. When taken in large quantities, these agents can interfere with cardiac function via sodium channel inhibition, and can be lethal in an overdose situation. ¹⁶

Several limitations of our review exist that warrant discussion. First, as with any review of this nature, it is possible that articles were inadvertently excluded as a result of inappropriate application of inclusion criteria. Second, the small number of trials included, especially with desipramine, significantly affect the generalizability of findings. Discrepancies between dosing regimens and intervals, and the measures by which efficacy in pain relief were assessed in each trial, make direct comparisons of outcomes difficult to ascertain.

Conclusions

Adjunctive analgesics to opioids have the ability to reduce opioid consumption while simultaneously providing pain relief through an alternative, complementary mechanism. While TCAs as a drug class have not proven to be overtly efficacious for this indication, desipramine, a secondary amine TCA, may have utility as an adjunctive analgesic in nociceptive pain due to its ability to potentially prolong the analgesic effects of opioids. Further research is warranted to determine the exact scope of desipramine use. Careful monitoring for anticholinergic adverse effects is necessary when using TCAs.