Non-Opioid Pharmacologic Options for Pain Numerous non-opioid pharmacologic therapies are available for pain, and these should be tried or considered, alone or in combination, before initiating long-term opioid therapy. 1 Acetaminophen (ACET) is used to treat mild- to-moderate pain without inflammation. All ACET products carry an FDA-required black box warning highlighting the potential for severe liver damage and potential for allergic reactions. 60 HCPs and patients should be aware of the dose levels from all prescribed and over-the-counter medication sources to avoid exceeding the recommended daily dosage. Nonsteroidal anti-inflammatory drugs (NSAIDs) include aspirin, ibuprofen, naproxen, and cyclooxygenase-2 (Cox-2) inhibitors and are used to treat mild-to-moderate pain and inflammation. Indications are numerous and include arthritis, bone fractures or tumors, muscle pains, headache, and acute pain caused by injury or surgery. 1 Nonselective NSAIDs are those that inhibit the activity of both COX-1 and COX-2 enzymes and can be associated with gastritis, gastric ulcers, and gastrointestinal (GI) bleeding. 1 COX-2 inhibitors have fewer GI adverse effects. 1 Risks are elevated with NSAIDs for heart attack, stroke, GI bleeding or perforation, and renal and cardiovascular abnormalities, particularly at higher doses and longer duration of use. 61 Anticonvulsants , such as gabapentin and pregabalin, have mild-to-moderate benefit for neuropathic pain syndromes, including postherpetic neuralgia and peripheral neuropathy and are also commonly used to treat migraine and as part of a multimodal approach to treating perioperative pain. 1 Adverse effects include drowsiness, cognitive slowing, 29 and a risk of misuse, particularly in people with a history of misusing opioids. 62 Gabapentin dose should be adjusted in chronic kidney disease. Antidepressants , including selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), and tricyclic antidepressants, are used in low doses for insomnia and neuropathic pain. Doses are typically lower for analgesia than those required to treat depression. SSRIs (e.g., fluoxetine, sertraline, citalopram, and paroxetine) have less analgesic effect compared with other antidepressant classes. 1 SNRIs (e.g., venlafaxine, duloxetine) are effective for a variety of chronic pain conditions, including musculoskeletal pain, fibromyalgia, and neuropathic pain, and are associated with less drowsiness, memory impairment, and cardiac conduction abnormalities than tricyclic antidepressants. Tricyclics (e.g., desipramine, nortriptyline, amitriptyline) are initiated at low doses and gradually titrated to effect. Depending on class, risks and adverse effects may include dry mouth, dizziness, sedation, memory impairment, orthostatic hypotension, urinary retention, cardiac conduction abnormalities, sexual dysfunction, weight gain, emotional blunting, and suicidal thoughts. 1,29 Second-generation tricyclic antidepressants (e.g., nortriptyline) tend to be better tolerated than first generation (e.g., amitriptyline). Withdrawal reactions are possible when antidepressants are suddenly stopped.
Musculoskeletal agents for pain and muscle spasm are for short-term use with sedation being a common adverse effect. Common medications used in pain treatment include baclofen, tizanidine, and cyclobenzaprine. Particular risks are notable with carisoprodol (toxicity, unclear therapeutic benefit) and benzodiazepines (SUD, respiratory depression leading to overdose) when prescribed in combination with opioids. 29 Considering the risks with carisoprodol and benzodiazepines and the availability of other agents, these medications are not recommended to treat pain from muscle spasm. 1 Topical medications include lidocaine, ketamine, capsaicin, and anti-inflammatory drugs such as ketoprofen and diclofenac. Anti-inflammatory topicals are proven beneficial for musculoskeletal pain, as is capsaicin for neuropathic pain. 29 Cannabis remains a Schedule I drug in the United States, defined by the Drug Enforcement Administration (DEA), as having no currently accepted medical use and a high potential for abuse. 1 Rigorous studies are lacking on the safety and efficacy of any specific cannabis product as a treatment for pain. 1 Expert views and systematic reviews 63,64 differ regarding the strength and quality of evidence for cannabis use, and the IASP does not endorse general use of cannabinoids for pain, citing lack of high-quality research. The evidence remains inconclusive to recommend the general use of cannabis for pain.
Little is known about the safety, efficacy, dose, and routes of administration of available cannabis products. Epidiolex (cannabidiol) [CBD] oral solution has been approved for the treatment of seizures associated with two rare and severe forms of epilepsy, Lennox-Gastaut syndrome and Dravet syndrome, in patients age 2 and older. 65 (It is THC that has the primary psychoactive component of marijuana, not CBD). Importantly, the FDA has not approved cannabis for the treatment of chronic pain. 63 However, a number of patients with pain appear to be replacing opioids with cannabis. Marijuana is legal for medical use in several states, and public interest in cannabis and cannabis-derived products for pain treatment is rising. 63 Adverse events reported with cannabis use include psychotomimetic effects, anxiety and psychosis, cognitive dysmotivational syndrome, and learning deficits in adolescents. 66 Cannabis can also have hyperemesis effects, impair driving safety, and is linked to vascular events. 66 The topic of concurrent cannabis and opioid use will be covered later in this activity. Opioids for Pain Opioid analgesic effects are principally achieved by the opioid binding to and activating mu, kappa, and delta receptors in the endogenous opioid system. Drugs are classified according to their action at these receptors as full agonists, mixed agonist-antagonists, or antagonists (Table 2).
Table 2. Opioid Analgesic Classifications
Type
Generic Name
Notes/Cautions
Pure agonists
Codeine Dihydrocodeine Fentanyl Hydrocodone Hydromorphone Levorphanol Meperidine* Methadone Morphine Oxycodone Oxymorphone Propoxyphene
*Meperidine not recommended for long-term treatment or in patients with renal compromise due to toxicity risks
Agonist-antagonists Partial agonist: Buprenorphine
May produce withdrawal if started while patient receiving full opioid agonist
Mixed agonist-antagonists: Butorphanol Dezocine
Nalbuphine Pentazocine Naloxone Naltrexone Tramadol Tapentadol
Pure antagonists
Administered to reverse opioid effects
Other
Dual action mu-agonist and serotonin– norepinephrine reuptake inhibitor Dual action mu-agonist and norepinephrine reuptake inhibitor
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