A Practical Approach to Using Adjuvant Analgesics in Older Adults

Russell K. Portenoy, MD

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

Drugs Used for Musculoskeletal Disorders

Common musculoskeletal pains, such as multifocal joint pain and low back pain, are highly prevalent in older adults. The multipurpose adjuvant analgesics that could potentially be used for these disorders include antidepressants, tizanidine, cannabinoids, and botulinum toxin. Although a group of drugs known as so-called muscle relaxants, including methocarbamol, carisoprodol, chlorzoxazone, metaxalone, and cyclobenzaprine, are approved for acute musculoskeletal pain in the United States, they do not directly relax skeletal muscle and have no evidence of efficacy in chronic pain.^[65] Given the potential for adverse effects in older adults, these drugs are not favored for chronic pain.

Muscle pain occurs with fibromyalgia and chronic widespread pain, and when severe enough to interfere with quality of life, pharmacotherapy should be considered. Evidence-based guidelines support trials of the analgesic antidepressants, particularly duloxetine and TCAs, and the gabapentinoids, particularly pregabalin.^[66]

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Abstract and Introduction
Approach to the Adjuvant Analgesics for Chronic Pain
Multipurpose Adjuvant Analgesics
Drugs Used for Neuropathic Pain
Drugs Used for Musculoskeletal Disorders
Drugs Used in Cancer Pain Management
References

Table 1. Minimizing Risk in the Use of the Adjuvant Analgesics
1. Consider whether nonpharmacologic approaches to pain management can be used and potentially obviate the need for drugs. 2. Consider whether topical drug therapies can be tried and potentially obviate the need for systemic adjuvant analgesic therapy. 3. If a systemic drug may be useful, review the patient's current drug regimen and consider deprescribing drugs that have unclear benefit. 4. Select an orally administered adjuvant analgesic for a trial based on type of pain, conventional practice, and risks associated with the potential for adverse effects including drug-drug interactions. 5. In prescribing an adjuvant analgesic, be sure that prescribing information (starting dose, titration guidelines, maximum dose, monitoring) applies to the use of the drug for pain; if uncertain, check the literature. 6. Modify the conventional prescribing information to augment caution (low starting dose, slower titration, additional monitoring). 7. Have clear end points for evaluating effectiveness (eg, pain relief and side effects after titration to the conventional maximum dose or the dose associated with minor side effects). 8. If the drug is ineffective, eliminate it but be cognizant of the potential for discontinuation syndromes with some drug classes (eg, antidepressants). 9. Educate the patient and caregivers that the use of these drugs is a trial-and-error process that requires time and careful monitoring.

Table 2. Adjuvant Analgesics
	Category
	Class	Type	Examples	Comment
Multipurpose analgesics	Antidepressants	SNRIs Secondary amine TCAs Tertiary amine TCAs SSRIs	Duloxetine, milnacipran, venlafaxine, desvenlafaxine Desipramine, nortriptyline Amitriptyline, imipramine Paroxetine, citalopram	Established analgesics; duloxetine often selected first for chronic pain Established analgesics; better tolerated than the tertiary amine TCAs Established analgesics Poor evidence of analgesia
	Alpha-2 adrenergic agonists		Tizanidine, clonidine, dexmedetomidine	Tizanidine is oral and better tolerated than clonidine Clonidine used in spinal infusions; dexmedetomidine is used in critical care
	Cannabinoids	Pharmaceutical Nonpharmaceutical	Nabiximols, nabilone, dronabinol Medical cannabis	Nabiximols not available in the United States; limited evidence for others Available in many states
	Glucocorticoids		Dexamethasone, prednisone	Commonly used in advanced cancer for pain/other symptoms
	NMDA receptor antagonists		Ketamine, memantine, amantadine, dextromethorphan	Evidence mixed but commonly used in palliative care for severe opioid-refractory pain. Efficacy in depression may increase use
	Neuroleptics	First/second generation	Haloperidol, olanzapine	Poor evidence of efficacy
	Topical agents	Local anesthetics NSAIDs Capsaicin Compounds	Lidocaine 5% patch or cream, and lower concentration creams, gels, and patches Diclofenac ketoprofen .075% patch or cream, 8% patch Ketamine, amitriptyline, menthol, others	5% patch used for neuropathic and musculoskeletal pain Approved for acute musculoskeletal pains .075% used for neuropathic or musculoskeletal pain; 8% patch may relieve PHN for months after short exposure in a monitored setting Limited evidence, costly; safety supports trials if available
	Botulinum toxin	Botulinum A, B		Evidence for use in many focal and regional neuropathic and musculoskeletal pain
Drugs used for neuropathic pain	Multipurpose adjuvant analgesics	Antidepressants, α-2 adrenergic agonists, cannabinoids and other systemic drugs, topical drugs, botulinum toxins	See above	Most guidelines emphasize the antidepressants, the gabapentinoids, and the topical drugs for neuropathic pain; glucocorticoids are commonly used for neuropathic pain in advanced cancer
	Gabapentinoids		Pregabalin, gabapentin	Evidence in acute pain and chronic neuropathic pain; used first for neuropathic pain, unless comorbid depression supports antidepressant
	Other anticonvulsants		Oxcarbazepine, lacosamide, topiramate	Older drugs may be analgesic, but side effects support use of newer drugs; limited evidence overall
	GABA agonists	GABA_A GABA_B	Clonazepam Baclofen	Poor evidence of analgesia
	Sodium channel blockers		IV lidocaine, mexiletine	IV lidocaine used for pain in monitored settings; oral drugs not used for pain due to limited evidence and side effects
Drugs used for musculoskeletal pains	Multipurpose adjuvant analgesics	Antidepressants, alpha-2 adrenergic agonists, cannabinoids, topical drugs, botulinum toxins	See above
	So-called muscle relaxants		Methocarbamol, carisoprodol, chlorzoxazone, metaxalone, cyclobenzaprine	No evidence in chronic pain; not used for chronic pain due to side-effect liability
Drugs used for cancer-related bone pain	Osteoclast inhibitors	Bisphosphonates RANKL inhibitor Calcitonin	Zoledronate, alendronate, ibandronate, Denosumab	Used to prevent and treat pain and other SREs Poor evidence of efficacy
	Radioisotopes		Samarium-153, strontium-89, phosphorus-32, others
Drugs used for pain and other symptoms in cancer-related bowel obstruction	Multipurpose adjuvant analgesics	Glucocorticoid	Dexamethasone	Most patients receive a glucocorticoid and an opioid
	Antiemetics	Dopamine antagonist, 5-HT₃ antagonist	Metoclopramide, haloperidol, ondansetron, granisetron
	Antisecretory drugs	PPI, H2 blockers Anticholinergic drug Somatostatin analog	Omeprazole, ranitidine Scopolamine, glycopyrrolate Octreotide, lanreotide	Risk of cognitive side effects probably lessened by using drug with poor BBB penetration (ie, scopolamine, butylbromide, or glycopyrrolate) Evidence of efficacy is mixed and may not be a first-line approach for this reason

Abbreviations: 5-HT, 5 hydroxytryptamine or serotonin; BBB, blood-brain barrier; GABA, gamma-aminobutyric acid; NMDA, N-methyl-D-aspartate; NSAIDs, nonsteroidal anti-inflammatory drugs; PHN, postherpetic neuralgia; PPI, proton pump inhibitor; RANKL, receptor activator of nuclear factor-κB ligand; SNRIs, serotonin norepinephrine reuptake inhibitors; SREs, skeletal-related events; SSRIs, serotonin selective reuptake inhibitors; TCAs, tricyclic antidepressants.