A Practical Approach to Using Adjuvant Analgesics in Older Adults

Russell K. Portenoy, MD

Disclosures

J Am Geriatr Soc. 2020;68(4):691-698. 

In This Article

Multipurpose Adjuvant Analgesics

Multipurpose adjuvant analgesics include systemic drugs, topical agents, and botulinum toxin injection. The systemic drugs include selected antidepressants, alpha-2 adrenergic agonists, cannabinoids, glucocorticoids, neuroleptics, and N-methyl-D-aspartate (NMDA) inhibitors.

Analgesic Antidepressants

Selected antidepressant drugs are potentially analgesic in varied types of chronic pain including neuropathic pain conditions, musculoskeletal pains, and headache.[11–13] Analgesic effects are well established for the serotonin-norepinephrine reuptake inhibitors (SNRIs) and the tricyclic antidepressants (TCAs). Among the SNRIs, the evidence is strongest for duloxetine and less robust for milnacipran, venlafaxine, and desvenlafaxine. Both tertiary amine TCAs (eg, amitriptyline and imipramine) and secondary amine TCAs (eg, desipramine and nortriptyline) are analgesic. The selective serotonin reuptake inhibitors, such as fluoxetine, and other antidepressants, such as bupropion and mirtazapine, lack comparable evidence of analgesic efficacy.

The SNRIs appear generally safer than the TCAs, particularly the tertiary amine TCAs.[14] The latter drugs are characterized by significant anticholinergic effects, orthostatic hypotension, sedation, and impaired cardiac conduction; these effects raise concern about use in older adults, even at the relatively low doses used for analgesia. Accordingly, duloxetine often is considered first. If an alternative is needed, possibilities include other SNRIs, such as milnacipran, and either desipramine or nortriptyline. To reduce the risk of adverse effects, treatment usually is initiated with the lowest available dose, irrespective of the drug. Dose escalation should employ small increments at intervals that allow an adequate period of observation, usually at least a week at each dose level. The analgesic dose is comparable with the antidepressant dose for the SNRIs and potentially lower than the antidepressant dose for the TCAs. If treatment must be stopped, dose tapering is advisable to reduce the risk of a discontinuation syndrome.[15] The potential for a discontinuation syndrome underscores the importance of cautious patient selection (limited to clinically significant chronic pain) and careful monitoring during dose reduction.

The Alpha-2 Adrenergic Agonists

Although the evidence is limited, analgesic effects were demonstrated for all commercially available alpha-2 adrenergic agonists including clonidine, tizanidine, and dexmedetomidine.[16–18] Tizanidine is likely to be better tolerated than clonidine and generally considered a second-line multipurpose adjuvant analgesic. It can cause somnolence, mental clouding, and orthostasis, however, and must be used cautiously in older adults. Treatment is usually initiated with a small nighttime dose of 2 mg that is slowly increased. Effective doses may be as high as 24 mg per day in divided doses. An uncommon acute withdrawal syndrome, manifest primarily as adrenergic hyperactivity, has been reported following treatment discontinuation; if possible, the dose should be tapered before treatment is stopped.

Cannabinoids

Nabiximols, an oromucosal spray containing mostly delta (9)-tetrahydrocannabinol (THC) and cannabidiol, has some efficacy in opioid-refractory cancer pain.[19,20] It is available in some countries for this indication or for spasticity due to multiple sclerosis. Two oral cannabinoids, dronabinol and nabilone, are currently available in the United States, but data relative to pain are very limited.[21–23] These drugs are rarely considered for a pain-related indication. Cannabis itself has analgesic efficacy in some studies, and medical cannabis is now available in more than 30 states. A scoping review of 72 systematic reviews concluded there was some evidence of efficacy for cannabis-based products in chronic pain of different types, but results are inconsistent and conclusions not possible.[24] The use of medical cannabis in older adults was recently reviewed.[25]

Glucocorticoids, NMDA Antagonists, and Neuroleptics

Other multipurpose analgesics have more limited utility given the quality of the evidence or potential risks. Although glucocorticoids are analgesic in many inflammatory conditions, they are not used routinely for pain due to the risks associated with higher doses and longer treatment durations. These risks are generally considered acceptable in the population with advanced cancer, however, and based on limited evidence[26,27] and extensive experience, a glucocorticoid, usually dexamethasone in the United States, is commonly given for cancer-related pain and other symptoms. In most situations, treatment starts with a loading dose of 10 to 20 mg, followed by 1 to 2 mg twice/day.

The NMDA receptor antagonists include ketamine, memantine, amantadine, and dextromethorphan. Methadone is commercially available in most countries as a racemate containing two isomers, one of which, the d-isomer, is an NMDA antagonist. Data pertaining to the primary NMDA antagonists are minimal for all except ketamine, and numerous analgesic studies of parenteral ketamine regimens have yielded conflicting results.[28–32] Although evidence of efficacy in refractory depression[33] may increase interest in ketamine, the risk of serious adverse effects, such as psychotomimetic experiences and hypertension, combined with the lack of experience with a commercially available oral formulation,[34] constrain its broader use. At present, ketamine is used as an analgesic by specialists in palliative care, pain management, and emergency medicine.[32,35,36]

A systematic review of controlled trials found very limited evidence of analgesic efficacy for selected neuroleptics.[37] Given the potential for adverse effects in older adults, these drugs should not be considered for pain.

Topical Analgesics

The low systemic absorption of topical therapies imparts high safety, and these drugs should be considered whenever feasible in older adults with chronic pain. One review found strong evidence of topical analgesia for two NSAIDs, diclofenac and ketoprofen, in musculoskeletal pain; moderate-quality evidence for high-concentration capsaicin in postherpetic neuralgia; and limited evidence for lidocaine, other NSAIDs, salicylate, low-concentration capsaicin, clonidine, and herbal remedies.[38]

Topical local anesthetics are the most widely used treatments. Various nonprescription creams, gels, and patches are available at various concentrations up to 4%; formulations that deliver more lidocaine to the skin are available by prescription including two proprietary patches and creams. The prescription patches, approved for postherpetic neuralgia using a 12 hour per day dosing regimen, are commonly considered off-label for any type of focal pain. Based on a pharmacokinetic study demonstrating low systemic absorption[39] and clinical experience, some experts also recommend changing the patch every 24 hours and using two patches if necessary to cover the painful area.

Capsaicin, a naturally occurring compound that inhibits primary sensory neurons, is available in low-concentration (.075%) creams or patches and a high-concentration (8%) patch. Limited data suggest that the low-dose formulations may be helpful in focal neuropathic or musculoskeletal pains.[40] The high-dose patch, administered for a short time in a monitored setting, is approved for postherpetic neuralgia in the United States and peripheral neuropathic pain in the European Union.[41]

Compounding pharmacies offer other topical formulations that may include amitriptyline, doxepin, baclofen, ketamine, gabapentin, or menthol either alone or in combinations. Evidence in support of these treatments is very limited, and cost is a barrier for many patients. Nonetheless, these compounds are relatively safe, and if available to the patient, trials may be considered. One controlled trial found a strong trend supporting the efficacy of a gel containing baclofen 10 mg, amitriptyline 40 mg, and ketamine 20 mg for neuropathic symptoms associated with chemotherapy-induced peripheral neuropathy[42] and another small study favored menthol 1% in cancer-related neuropathic pain.[43] Topical morphine is used by some specialists in palliative care for pain associated with pressure ulcers or mucosal lesions.[44]

Botulinum Toxins

Botulinum toxins block acetylcholine release at the neuromuscular junction and have a variety of other actions that may mitigate pain.[45] There is evidence that injection of botulinum toxin can yield analgesia in peripheral neuropathic pain, plantar fasciitis, piriformis syndrome, postsurgical pain, joint pain, low back pain, pain due to osteoarthropathy, and pain associated with varied cancer-related posttreatment syndromes.[46–48] It is an approved therapy for migraine and relieves pain due to muscle spasticity. Adverse effects are very uncommon, and if cost and availability can be managed, botulinum toxin injection may be considered for diverse types of chronic pain in older adults.

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