Amitriptyline is a tricyclic antidepressant that research has identified as being useful for the treatment of peripheral neuropathy symptoms and neuropathic pain. For the non-cancer population, it has been used as a treatment for eating disorders and migraine headaches. Amitriptyline is available as a tablet to take by mouth. It may take weeks to build up in the system in order for one to feel the full benefits of the drug, and suddenly stopping use can cause symptoms of withdrawal. Amitryptyline has been evaluated for its effects in peripheral neuropathy and, as an antidepressant, it has relevance for the topic of depression.
Kautio, A.L., Haanpaa, M., Leminen, A., Kalso, E., Kautiainen, H., & Saarto, T. (2009). Amitriptyline in the prevention of chemotherapy-induced neuropathic symptoms. Anticancer Research, 29, 2601–2606.
The purpose of the study was to determine if amitriptyline would be effective in treating chemotherapy-induced peripheral neuropathy (CIPN) compared to placebo.
Patients were allocated to amitriptyline or placebo groups. Treatment was started at 25 mg per day, and doses were elevated 25 mg per week up to a maximum dose of 100 mg per day if tolerated. Treatment was continued until the end of the neurotoxic chemotherapy. Follow-up visits were performed every two months and patients were asked to maintain a diary in which they graded neutopathic symptoms by a visual analog scale twice a week. The primary end point was the appearance or progression of neuropathic symptoms based on diary data.
The study was conducted in an outpatient, single-site setting in Helsinki, Finland.
The study was designed as a double blind, randomized, placebo-controlled parallel group.
Measurements include the National Cancer Institute's Common Terminology Criteria for Adverse Events, the European Organisation for the Research and Treatment of Cancer C30 quality-of-life measure, and a visual analog scale for symptom grading.
The median follow-up was at 19–21 weeks. Seventy-four percent of patients were on the highest dose of amtriptyline, which was well tolerated. Tiredness was the most frequent reason for dose reduction. In addition, no differences were noted in intensity of neuropathy between groups. In the majority of cases, the intensity of neuropathy was mild at grade 1. Neuropathy was seen in 76% of patients after nine cycles of treatment. Because of a lack of effect, the study was discontinued earlier than planned.
The study did not demonstrate any effect by amitriptyline on the prevention or treatment of CIPN.
The findings from this study do not support the use of amitriptyline for the prevention and management of CIPN.
Mishra, S., Bhatnagar, S., Goyal, G.N., Rana, S.P., & Upadhya, S.P. (2012). A comparative efficacy of amitriptyline, gabapentin, and pregabalin in neuropathic cancer pain: A prospective randomized double-blind placebo-controlled study. American Journal of Hospice and Palliative Care, 29, 177–182.
To compare the efficacy of amitryptylline, gabapentin, and pregabalin in patients with cancer experiencing neuropathic pain
Patients were randomly assigned to amitryptyllin (AT), gabapentin (GB), pregabalin (PG), or placebo. AT was given at 50 mg/day for one week, then increased incrementally to 100 mg/day. GB was given at 900 mg/day for one week in divided doses, then increased to 1,800 mg/day by week 3. PG was given at 150 mg/day for one week, then increased to 600 mg/day by week 3. The control group received placebo capsules. Morphine was used as rescue pain medication as needed. Patients were evaluated weekly for four weeks.
The study has clinical applicability for late effects and survivorship.
The study was a placebo-controlled, randomized trial.
VAS scores decreased in all groups. In week 4, those on pregabalin had significantly lower VAS scores than other groups, and scores declined by 4–5 points (p < 0.03). By the third visit, the percentage of patients who required morphine rescue increased: 46.7% with AT, 23.3% with GB, 16.7% with PG, and 100% with placebo. Lancinating pain incidence was lowest in the PG group. There were significantly fewer patients with dysesthesia in the PG group (6.7%) compared to the GB and placebo groups after four weeks. The percentage of patients with allodynia declined in all groups. The PG group showed a statistically significant improvement in ECOG score compared to all other groups (p < 0.001). Satisfaction was similar in all groups, and there were no significant differences in adverse reactions, with a gradual increase in all groups over time. Adverse effects were somnolence, dizziness, nausea, constipation, and dry mouth.
All of the drugs tested here demonstrated some efficacy in improving neuropathic symptoms. In several areas, it appears that pregabalin was more effective than gabapentin, opioid monotherapy, and amitryptylline. All medications were given in combination with opioids for pain management.
All of the medications examined in this study were effective and had a morphine-sparing effect in the treatment of neuropathic pain and other symptoms. Pregabalin was more effective than other alternatives tested in some areas. As all patients in this study received opioids for pain rescue, it should be noted that essentially all medications compared were given in combination with opioids.
Stubblefield, M.D., Burstein, H.J., Burton, A.W., Custodio, C.M., Deng, G.E., Ho, M., . . . Von Roenn, J.H. (2009). NCCN task force report: Management of neuropathy in cancer. Journal of the National Comprehensive Cancer Network, 7(Suppl., 5), S1–S26.
This study outlines the common antineoplastic agents known to cause neuropathy and provides information on incidence, onset dosages, the signs and symptoms, and general course and patterns of resolution. Agents identified include platinum compounds, vinca alkaloids, taxanes, bortezomib, ixabepilone, thalidomide, and lenalidomide. In addition to outlining the mechanisms of neuropathy development in cancer, the study discusses neurophysiologic and objective testing, noting that findings on electromyographic (EMG) and nerve conduction studies (NCS) can lag behind clinical symptoms. The study also identifies commonly used physician-based grading systems, including the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) and Eastern Cooperative Oncology Group (ECOG) systems, and notes that these two grading systems lack inter-rater reliability. Patient-based instruments for assessment include the Functional Assessment of Cancer Treatment (FACT) and the Patient Neurotoxicity Questionnaire (PNQ). The authors note that the routine assessment of pain secondary to neuropathy, using instruments such as the Brief Pain Inventory (BPI), is useful.
Routine assessment should be conducted and continued throughout therapy. Key points in assessment that should be included are:
Proposed agents for prevention of CIPN identified include:
Agents used for pain management:
Current literature is inconclusive on the benefits of neurostimulation in treating CIPN. The authors note that evidence is scarce on efficacy of complimentary and alternative medicine (CAM) therapies and the need for appropriately powered and controlled studies in this area. However, acupuncture was identified as a promising adjunct option. The article also provides safety tips and issues for management of functional deficits in PIN, including situations in which to avoid or discontinue physical training, footwear selection, orthosis, and safety aspects of the household environment. Finally, the article addresses how autonomic neuropathy from chemotherapy occurs, but has not been well documented or studied.
The article provides a comprehensive review of current knowledge about CIPN and common approaches toward assessment, prevention, and management. The authors do not make specific recommendations for treatment, research to validate evaluation tools, and exploration of combinations and scheduling of pain medications. In addition, testing of the safety and effectiveness of therapeutic interventions and dietary supplements are needed.