Acetaminophen is one of the most widely used analgesics in the world and a first-line treatment for mild to moderate pain. Unlike NSAIDs, it has no significant anti-inflammatory effect, but it is gentler on the stomach and cardiovascular system. It is the preferred analgesic for older adults and patients who cannot tolerate NSAIDs.

Ibuprofen and naproxen are non-steroidal anti-inflammatory drugs (NSAIDs) available without a prescription. They reduce both pain and inflammation by inhibiting the cyclooxygenase (COX-1 and COX-2) enzymes that produce prostaglandins — the chemical mediators responsible for pain, swelling, and fever.

Meloxicam is a prescription NSAID that preferentially inhibits COX-2 over COX-1, providing anti-inflammatory and analgesic effects with somewhat less GI irritation than traditional NSAIDs. It is taken once daily, which improves adherence. It is one of the most commonly prescribed pain medications in primary care and pain medicine.

Celecoxib is a selective COX-2 inhibitor designed to provide the anti-inflammatory benefits of an NSAID while sparing the GI tract by avoiding inhibition of COX-1, the enzyme that protects the stomach lining. It is particularly valuable for patients who need NSAID therapy but have a history of ulcers, GI intolerance, or are at high GI risk.

Diclofenac is a prescription NSAID available in multiple formulations: oral tablets (Voltaren, Zipsor), an oral powder dissolved in water for acute migraine (Cambia), and a topical gel (Voltaren Arthritis Pain, also available OTC). The topical form is particularly useful because it achieves effective tissue concentrations at the joint with minimal systemic absorption, greatly reducing GI, cardiovascular, and kidney risks.

Etodolac is a prescription NSAID that preferentially inhibits COX-2 over COX-1 at therapeutic doses, providing effective anti-inflammatory and analgesic activity with a somewhat reduced risk of GI irritation compared to non-selective NSAIDs. It is well-suited for patients with chronic musculoskeletal conditions who require consistent anti-inflammatory coverage and may not tolerate older non-selective agents. Etodolac is available in immediate-release and extended-release formulations.

Gabapentin is one of the most commonly prescribed medications for neuropathic (nerve) pain. Originally developed as an anticonvulsant, it was found to be highly effective for pain arising from damaged or sensitized nerves. It is FDA-approved for postherpetic neuralgia (shingles pain) and is widely used off-label for radiculopathy, diabetic neuropathy, fibromyalgia, and other nerve pain conditions.

Pregabalin is a gabapentinoid with a similar mechanism to gabapentin but more predictable absorption, allowing twice-daily dosing. It is FDA-approved for diabetic neuropathy, postherpetic neuralgia, fibromyalgia, and spinal cord injury pain. Many patients who have an incomplete response to gabapentin respond well to pregabalin, and vice versa.

Serotonin-norepinephrine reuptake inhibitors (SNRIs) are antidepressants that also have significant independent analgesic effects. Duloxetine is FDA-approved for diabetic neuropathy, fibromyalgia, chronic musculoskeletal pain, and major depression. It is one of the most evidence-supported non-opioid medications for chronic pain and is a first-line treatment in multiple pain medicine guidelines.

Milnacipran is an SNRI FDA-approved exclusively for fibromyalgia management. Unlike duloxetine and venlafaxine, milnacipran inhibits norepinephrine slightly more than serotonin — a profile that may be particularly suited to fibromyalgia’s pain and fatigue symptoms. It is used primarily when duloxetine has not provided sufficient fibromyalgia control.

Tricyclic antidepressants (TCAs) were among the first medications proven effective for neuropathic pain. At the low doses used in pain medicine (typically 10–75 mg at bedtime — far below antidepressant doses of 150–300 mg/day), they provide analgesia, improve sleep architecture, and can prevent migraines and tension headaches. Nortriptyline is the active metabolite of amitriptyline and is generally better tolerated.

Cyclobenzaprine is the most widely prescribed muscle relaxant in the United States. It is structurally related to tricyclic antidepressants and works centrally in the brainstem rather than directly on muscle tissue. It is most effective for acute muscle spasm associated with musculoskeletal injuries. Extended-release formulations (Amrix) allow once-daily dosing.

Tizanidine is a centrally acting muscle relaxant with a mechanism distinct from cyclobenzaprine. It is an alpha-2 adrenergic receptor agonist that reduces the release of excitatory neurotransmitters at the spinal cord level. It is particularly effective for spasticity (in neurological conditions like multiple sclerosis or spinal cord injury) and for chronic muscle pain and spasm.

Baclofen is a GABA-B receptor agonist that reduces spinal cord reflex activity and is the primary treatment for spasticity of spinal cord origin. It is widely used in neurology and pain medicine for conditions involving spinal cord injury, MS, and spastic cerebral palsy. Intrathecal baclofen (ITB) — delivered directly into the spinal fluid via an implanted pump — is used for severe spasticity uncontrolled by oral medication.

Methocarbamol is a centrally acting muscle relaxant with a generally favorable side effect profile compared to cyclobenzaprine and tizanidine. It produces less sedation, making it preferable for patients who need to remain alert during the day. It is available in oral and intravenous formulations.

The lidocaine 5% patch delivers a local anesthetic directly to a painful area through the skin, providing localized pain relief with minimal systemic exposure. It is FDA-approved for postherpetic neuralgia (shingles pain) and is widely used off-label for other localized neuropathic pain conditions. Systemic absorption is minimal (<5% of the total lidocaine dose), and systemic toxicity is rare when used as directed.

Topical diclofenac provides anti-inflammatory and analgesic effects at a specific joint or soft-tissue area while delivering only a small fraction of the systemic exposure of oral NSAIDs (<6% of the oral dose). This makes it ideal for patients who benefit from NSAIDs but have GI, cardiovascular, or kidney concerns with oral formulations. Voltaren Arthritis Pain gel is now available over the counter; the Flector patch requires a prescription.

Capsaicin cream is derived from capsicum (chili pepper) and works by depleting substance P — a key neurotransmitter involved in transmitting pain signals — from peripheral nerve endings in the skin. With repeated application, the nerve endings in the treated area become desensitized, providing progressive and cumulative pain relief. Available over the counter in concentrations of 0.025% to 0.1%, capsaicin cream is an accessible first-line topical option for localized pain.

Compounded topical analgesics are custom-mixed preparations created by a compounding pharmacy to combine two or more analgesic agents in a single cream or gel base. By combining agents with different mechanisms (e.g., a local anesthetic + NSAID + membrane stabilizer), compounded topicals can address multiple pain pathways simultaneously at the local level, with minimal systemic effects. Common formulations include combinations of lidocaine, diclofenac, ketamine, gabapentin, baclofen, and cyclobenzaprine.

Triptans are serotonin (5-HT1B/1D) receptor agonists and the most effective class of acute migraine medications. They work by constricting dilated cranial blood vessels, blocking nociceptive trigeminal nerve terminals, and reducing the release of inflammatory neuropeptides that drive migraine pain. Available in oral, nasal spray, and injectable forms, triptans can abort a migraine attack when taken early.

Calcitonin gene-related peptide (CGRP) is a neuropeptide that plays a central role in migraine pathophysiology. Anti-CGRP monoclonal antibodies — the first migraine-specific preventive treatments ever developed — block either the CGRP protein itself or its receptor to prevent the cascade that triggers migraine. They are administered monthly (or quarterly for Ajovy and Emgality) by subcutaneous injection and represent a major advance in migraine prevention.

Gepants are small-molecule CGRP receptor antagonists available in oral form. Unlike triptans, gepants do not cause vasoconstriction, making them safe for patients with cardiovascular conditions that preclude triptan use. This class now includes three agents with distinct indications: ubrogepant (Ubrelvy) for acute treatment, rimegepant (Nurtec ODT) for both acute treatment and prevention, and atogepant (Qulipta) exclusively for migraine prevention.

Short-acting opioids provide pain relief for 4–6 hours and are used for breakthrough pain in patients on scheduled opioid therapy, or for acute pain management of limited duration. They include oxycodone IR (Roxicodone®, also available in combination with acetaminophen as Percocet®), hydrocodone (Norco®, Vicodin®), tramadol (Ultram®), and codeine. Tramadol has a dual mechanism — weak opioid agonism plus serotonin/norepinephrine reuptake inhibition.

Long-acting opioids provide sustained around-the-clock analgesia for patients with continuous, moderate to severe chronic pain not adequately managed by non-opioid analgesics. They include extended-release oxycodone (OxyContin®), extended-release morphine (MS Contin®, Kadian®), extended-release hydromorphone (Exalgo®), and the buprenorphine transdermal patch (Butrans®). Buprenorphine is a partial opioid agonist with a pharmacological ceiling effect on respiratory depression, which may offer a safety advantage compared to full agonists, though overdose risk still exists.