Considerations for Nonopioid Pain Management

The opioid pendulum never stops; thus, it’s important to wrap our clinician heads around nonopioid pain medications as a foundational treatment within modern pain management, offering effective symptom control while avoiding many of the risks associated with opioids, despite their own “baggage.”

The primary nonopioid pain medications, of course, include acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs), along with the novel suzetrigine, and are complemented by adjuvant medications such as antidepressants, muscle relaxants, and gabapentinoids. Together, these therapies support a multimodal, mechanism-based approach to safe and effective pain management patient care.

Acetaminophen

Acetaminophen (also known as paracetamol worldwide) is widely utilized for mild-to-moderate pain and fever. Its mechanism, although not concrete, is primarily central, involving inhibition of prostaglandin synthesis within the central nervous system, with no realized peripheral anti-inflammatory effects. This distinguishes it from NSAIDs and contributes to its favorable gastrointestinal (GI) safety profile. However, hepatotoxicity remains the major clinical concern, particularly at doses exceeding 4 grams daily in adults or at lower thresholds in patients with liver disease or chronic alcohol use, over-the-counter utilization, and patients of older age.

Acetaminophen overdoses account for over 50,000 emergency department visits in the US annually. However, one must appreciate that someone taking more of a medication than recommended is not the same as an adverse effect occurring at a recommended or initial starting dose. Despite this risk, when used appropriately, acetaminophen is recommended as a first-line option in many guidelines for osteoarthritis and acute pain. Recent systematic reviews suggest modest efficacy but strong safety when dosed correctly, reinforcing its role as a baseline analgesic.^1,2

Nonsteroidal Anti-Inflammatory Drugs

NSAIDs provide analgesic, antipyretic, and anti-inflammatory effects by inhibiting cyclooxygenase (COX)-1 and COX-2 enzymes, thereby reducing prostaglandin synthesis. This peripheral anti-inflammatory action makes NSAIDs particularly effective for musculoskeletal and inflammatory pain conditions. However, their use is limited by well-established adverse effects, including GI bleeding, cardiovascular events, and renal impairment. Risk varies by specific medication and patient characteristics; for example, COX-2 selective inhibitors may reduce GI toxicity but increase cardiovascular risk, and vice versa. Contemporary evidence emphasizes individualized NSAID selection using the lowest effective dose and shortest duration, particularly in high-risk populations.^3,4

Suzetrigine

Suzetrigine is a novel, selective voltage-gated sodium channel (Nav1.8) inhibitor designed to target peripheral nociceptive signaling while minimizing central nervous system effects, thereby offering a promising nonopioid approach to acute pain management. Clinical trial data showed comparable pain efficacy to low-dose hydrocodone/acetaminophen for postprocedural acute pain, which led to its FDA approval for acute pain in general. Its potential to mitigate chronic pain is being investigated further, as previous studies have not been favorable.

Other Adjuvant Medications

Adjuvant pain medications play a critical role in neuropathic and centralized pain states while also offering a “BOGO (buy one, get one)” patient-centered scenario. That is to say that a patient may be treated for depression or anxiety with an antidepressant while also experiencing pain, and lo and behold, the same antidepressant utilized for mental health can mitigate various painful conditions. Perhaps “TOGA (treat one, get another)” would be a more suitable acronym.

Antidepressants, particularly serotonin-norepinephrine reuptake inhibitors and tricyclic antidepressants (TCAs), enhance descending inhibitory pain pathways by increasing serotonin and norepinephrine levels in the central nervous system. Duloxetine and amitriptyline have demonstrated efficacy in conditions such as diabetic neuropathy and fibromyalgia, with respective FDA approvals. Notably, secondary TCAs (eg, nortriptyline, desipramine) tend to have fewer anticholinergic and sedative effects, improving tolerability, as long as the aim is to avoid or reduce adverse effects such as sedation.

Gabapentinoids, including gabapentin and pregabalin (and, technically, baclofen as a γ-aminobutyric acid [GABA] structural analog), modulate presynaptic calcium channels in the dorsal horn (ironically, not postsynaptic GABA receptors), reducing excitatory neurotransmitter release. They are particularly useful in neuropathic pain syndromes, though recent scrutiny highlights the inherent risks of sedation, dizziness, and potential misuse, especially when combined with other central nervous system depressants. Evidence supports their benefit in select populations, but careful patient selection is essential.⁵

Muscle relaxants are commonly utilized for acute musculoskeletal pain associated with muscle spasms or spasticity, as they are generally FDA approved for a maximum of 14 days, despite ubiquitous chronic utilization. These medications represent an “island of misfit medications” (think Rudolph the Red-Nosed Reindeer’s island of misfit toys) with various mechanisms not directly affecting muscle contractility, including spasticity-targeted central α-2 agonism (tizanidine, a cousin of clonidine) and GABA-mediated effects (baclofen). Along with spasm-targeted serotonin and norepinephrine (cyclobenzaprine, structurally a TCA); GABA (carisoprodol’s active metabolite is a barbiturate); and anticholinergic (orphenadrine is a diphenhydramine structural analog), among others with important patient counseling points such as methocarbamol potentially turning one’s urine green, chlorzoxazone can turn one’s urine purple. Metaxalone can be confused with metolazone (a diuretic). Although these “misfits” may provide short-term relief, their use is often limited by sedation, anticholinergic effects, and concerns in older adults, as the spasmodics are included in the Beers Criteria.⁶

Conclusion

Nonopioid medications are a pillar within a safe and effective pain management treatment plan, flanked by opioids, interventionals, and nonpharmacological options. Acetaminophen and NSAIDs remain first-line therapies, while adjuvant medications address specific pain mechanisms. Optimal use requires balancing efficacy with patient-specific safety considerations, reinforcing the importance of individualized, multimodal pain strategies.

REFERENCES

1. Bannuru RR, Schmid CH, Kent DM, Vaysbrot EE, Wong JB, McAlindon TE. Comparative effectiveness of pharmacologic interventions for knee osteoarthritis: a systematic review and network meta-analysis. Ann Intern Med. 2015;162(1):46-54. doi:10.7326/M14-1231

2. Machado GC, Maher CG, Ferreira PH, et al. Efficacy and safety of paracetamol for spinal pain and osteoarthritis: systematic review and meta-analysis of randomised placebo controlled trials. BMJ. 2013;382(9894):769-779. doi:10.1016/S0140-6736(13)60900-9

3. Coxib and traditional NSAID Trialists' (CNT) Collaboration; Bhala N, Emberson J, Merhi A, et al. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet. 2020;395(10241):769-781.

4. Kolasinski SL, Neogi T, Hochberg MC, et al. 2019 American College of Rheumatology/Arthritis Foundation Guideline for the Management of Osteoarthritis of the Hand, Hip, and Knee. Arthritis Care Res. 2020;72(2):149-162. https://www.arthritis.org/getmedia/d57cf9f5-e096-43a2-832d-dbc174065a58/Kolasinski-2020-american-college-of-rheumatology-a.pdf

5. Shanthanna H, Gilron I, Rajarathinam M, et al. Benefits and safety of gabapentinoids in chronic low back pain: A systematic review and meta-analysis of randomized controlled trials. PLoS Med. 2017;14(8):e1002369. Published 2017 Aug 15. doi:10.1371/journal.pmed.1002369

6. 2023 American Geriatrics Society Beers Criteria Update Expert Panel. American Geriatrics Society 2023 updated AGS Beers Criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2023;71(7):2052-2081. doi:10.1111/jgs.18372