Table 6. Adjuvant Analgesics for End-of-Life Pain Management 56
Drug Class
Agent
Route of Administration
Potential adverse effects
Indications
Antidepressants
Nortriptyline Desipramine Venlafaxine Duloxetine
Oral Oral Oral Oral Oral Oral Oral
Anticholinergic effects Cardiac arrhythmia
Neuropathic pain
Nausea, dizziness
Nausea
Anti-epilepsy drugs Gabapentin
Dizziness Dizziness Sedation
Neuropathic pain
Pregabalin Clonazepam
Corticosteroids
Dexamethasone
Oral/IV/Sq
“Steroid psychosis”
Neuropathic pain, cerebral edema, spinal cord compression, bone pain, visceral pain
Lidocaine
Lidocaine patch Lidocaine infusion
Topical
Erythema (rare)
Neuropathic pain
IV/sq
Perioral numbness, cardiac changes
Intractable neuropathic pain
NMDA antagonists Ketamine
Oral/IV/intranasal/ topical
Hallucinations
Unrelieved neuropathic pain; need to reduce opioid dose
Bisphosphonates
Pamidronate Clondronate Alendronate Zoledronic acid
IV IV
Pain flare, osteonecrosis
Osteolytic bone pain
Cannabinoids
Dronabinol (Marinol®) Nabilone (Cesamet® and Syndros®)
Oral Oral
Dizziness, nausea, tachycardia, euphoria
Pain, nausea, loss of appetite, spasticity
NMDA (dextromethorphan, amantadine, and ketamine) are believed to exert their analgesic effects by blocking receptors for glutamate and other excitatory amino acids at the level of the spinal cord. Ketamine is the most commonly-used agent, and can be administered intravenously, intramuscularly, subcutaneously, intranasally, sublingually, rectally, and topically. A general recommendation is to reduce the opioid dose by approximately 25% to 50% when starting ketamine to avoid sedation. 41 Psychotomimetic reactions consisting of hallucinations, vivid imagery delirium, confusion, and irrational behavior have been reported to occur in approximately 12% of individuals receiving the drug systemically. 42 Adverse effects, including hallucinations and unpleasant cognitive sensations, responded to diazepam at a dose of 1 mg intravenously. 42 antagonists In recent years there has been a resurgence of interest in the use of cannabinoids for the relief of pain and the end of life. Like opioids, cannabinoids produce their pharmacological effects via actions at specific receptors in the body that are designed for endogenously produced compounds with normal regulatory, homeostatic properties. 64 Unlike opioids, however, there has never been a documented case of death from cannabis overdose—indeed, cannabis has no known lethal dose. 65 The CB1 and CB2 receptors have been shown to mediate the analgesic effects of cannabinoids. 66 This has allowed for the development of more selective agents that may provide analgesia while minimizing cognitive or perceptual side effects. Two oral cannabinoid preparations are FDA-approved and available in the US (dronabinol and nabilone).
These routes of administration avoid the potential hazards and dosing uncertainties involved with inhaled or edible forms of cannabis. A review of the existing literature evaluating the role of cannabinoids currently approved for human use suggests that these agents are moderately effective for neuropathic pain with adverse effects that are less than or comparable to existing analgesics. 67 Cannabinoids have been shown to exert no appreciable effects on opioid plasma levels and may even augment the efficacy of oxycodone and morphine in patients suffering from a variety of chronic pain conditions, potentially allowing a reduction in the opioid doses used in such patients. 68 The authors of a review of the role of cannabinoids in hospice and palliative care concluded: “Many patients in a palliative care setting who are currently on long-term opioids for chronic pain could potentially be treated with either cannabis alone or in combination with a lower dose of opioids. From a pharmacological perspective, cannabinoids are considerably safer than opioids and have broad applicability in palliative care.” 64 Complementary/alternative strategies A wide range of complementary and alternative therapies (CAT) are commonly used in end-of-life care. 69 More than half of providers that offered CAT offered massage, supportive group therapy, music and pet therapy, guided imagery, and relaxation techniques. 70 Behaviors likely to respond to CAT interventions include: aggression, disruption, shadowing, depression, and repetitive behaviors (Table 7).
Interventions should be matched to the specific needs and capabilities of the patient, and they can be used concurrently with any medications that might be employed. 71,72 CAT interventions are aimed at reducing pain, inducing relaxation, and enhancing a sense of control over the pain or the underlying disease. Breathing exercises, relaxation, imagery, hypnosis, and other behavioral therapies are among the modalities shown to be potentially helpful to patients. 41 Physical modalities such as massage, use of heat or cold, acupuncture, acupressure, and other physical methods may be provided in consultation with physical or occupational therapy. These treatments can enhance patients’ sense of control as well as greatly reduce the family caregivers’ sense of helplessness when they are engaged in pain relief. One study found that both massage and “simple touch” induced statistically significant improvements in pain, quality of life, and physical and emotional symptom distress over time without increasing analgesic medication use. 79 Psychosocial interventions for end-of-life pain may include cancer pain education, hypnosis and imagery based methods, and coping skills training. 80 Educational programs are one of the most common interventions to address cancer pain barriers, and current studies provide high-quality evidence that pain education is feasible, cost-effective, and practical in end-of-life settings. 80 Coping skills training may be beneficial for patients and family caregivers dealing with chronic cancer pain, although the dose and components of a coping skills training regimen remain uncertain.
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