Nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, naproxen, diclofenac, and celecoxib are commonly used for chronic pain that arises from conditions involving inflammation like osteoarthritis. They work by inhibiting cyclooxygenase (COX) enzymes (COX-1 and COX-2), which are involved in the conversion of arachidonic acid into prostaglandins, chemicals that promote inflammation and pain. ^,

NSAIDs are particularly useful for musculoskeletal and joint pain, given the inflammatory mechanism typically involved in both. Over the counter availability of oral and topical formulations (diclofenac gel) makes access to these medications convenient for individuals without requiring a medical evaluation. However, prolonged use of NSAIDs for pain is known to increase the risk for gastrointestinal bleeding, renal dysfunction, and cardiovascular events, including stroke and myocardial infarction. ^,

Acetaminophen is another over-the-counter analgesic commonly used in mild-to-moderate chronic pain. Acetaminophen’s analgesic effect appears to arise from its metabolite p-aminophenol, which crosses the blood–brain barrier and is converted to arachidonoylaminophenol (AM404) by fatty-acid amide hydrolase. AM404 activates transient receptor potential vanilloid 1 (TRPV1) and cannabinoid receptor type 1 (CB1) receptor signaling in the brain and spinal dorsal horn and may inhibit sodium channels NaV1.7 and voltage-gated sodium channel nav1.8 (NaV1.8), preventing the firing of action potentials. ^, Acetaminophen is considered safer than NSAIDs for long-term use, especially for individuals with gastrointestinal, renal, or cardiovascular issues. Of note, liver toxicity may occur at high doses or with prolonged use, particularly in those with underlying liver disease or those with concurrent alcohol use.

Opioids such as morphine, oxycodone, and hydrocodone are potent pain relievers often used after surgery and for cancer pain when unrelieved by other medications. They work by binding to mu-opioid receptors in the brain and spinal cord to inhibit pain signals. Use of opioids for chronic pain has become controversial over the past 2 decades, with several guidelines suggesting use of opioids at the lowest dose required for the shortest duration feasible. Opioids are potent pain relievers, but the current literature for chronic use demonstrates limited improvement in functional outcomes and disability. Opioids also pose significant risks including tolerance and physical dependence, addiction, constipation, endocrine dysfunction, and opioid-induced hyperalgesia.

Antidepressants (eg, tricyclic antidepressants [TCAs] and serotonin-norepinephrine reuptake inhibitors [SNRIs]) and anticonvulsants (eg, gabapentin and pregabalin) have been shown to be effective in managing chronic pain.

Antidepressant medications affect neurotransmitters such as serotonin and norepinephrine, which are involved in pain regulation. Antidepressants provide relief for conditions such as neuropathic pain, musculoskeletal pain, and fibromyalgia. They also may be effective in patients with comorbid mood disorders as part of a multimodal pain management program. Limitations of antidepressants include the time taken for therapeutic effect, which may take weeks to provide benefit. Similarly, antidepressants may cause side effects, such as dizziness, dry mouth, weight gain, and fatigue. This is particularly true of TCAs.

Anticonvulsants, particularly gabapentinoids, are effective in treating neuropathic pain conditions such as diabetic neuropathy and are first-line medications. They reduce pain by decreasing neuronal excitability and transmission of peripheral pain signals. Similar to antidepressant medications, anticonvulsants may lead to sedation, weight gain, and fatigue.

Topical treatments, such as capsaicin, menthol, or lidocaine, can provide localized pain relief for multiple conditions, including osteoarthritis, musculoskeletal pain, and localized neuropathic pain. They are available in multiple formulations and can be applied directly over the area of pain. These properties allow reduced systemic side effects but also limit relief of deeper structures, such as the hip joint. Though these same properties limit systemic spread of medication, leading to minimal systemic side Capsaicin works to deplete substance P in nerve terminals. Lower concentrations of this medication are available over the counter, but higher concentrations (8%) should be applied in a supervised setting such as medical office. Menthol’s pain-relieving effect comes from its action on cold-sensing ion channels. Topically applied menthol selectively activates TRPM8 channels in peripheral sensory neurons, which produces an immediate cooling sensation and, after transient excitation, desensitizes nociceptors. Lidocaine works by blocking sodium channels in peripheral nerves. The 4% patch is available over the counter but the 5% patch is available by prescriptions only. Topical gels and creams are also available at variable concentrations.

A summary of medications commonly used for chronic pain is outlined in Table 1 .

Other nonopioid medication options for the management of pain include suzetrigine. Suzetrigine is a novel medication that was recently approved by the Food and Drug Administration (FDA) for acute pain which works by targeting a specific sodium channel that is largely expressed in peripheral sensory neurons. This medication decreases peripheral nociceptive signaling while sparing central nervous system functioning thereby avoiding common side effects of other pharmacologic agents that target pain (sedation and dizziness).

PT is an integral part of chronic pain management, especially for musculoskeletal pain conditions such as chronic back, knee, and shoulder pain. It is a first-line intervention for many chronic pain management conditions and poses few adverse effects. PT focuses on improving mobility, strength, flexibility, posture, and alignment, all of which can alleviate pain and prevent further injury. Strengthening improves muscular support of joints and reduces mechanical stress on joints while improving flexibility and range of motion of muscles. Stretching can also reduce muscle stiffness and reduce pressure on nerves.

There is strong evidence that regular aerobic exercise is essential in chronic pain management. Aerobic exercise works to reduce chronic pain through central and peripheral mechanisms. It enhances blood circulation, reduces inflammation, and promotes the release of neurotransmitters (endorphins and serotonin) that act as natural painkillers in the brain. Increased blood flow leads to improvement in oxygen and nutrient delivery to the body and enhances the removal of metabolic waste products that are implicated in chronic pain.

Furthermore, exercise can help combat the deconditioning that often occurs in people with chronic pain, leading to improved strength and stamina. This leads to reduced pain, improved functional capacity, and overall improvements in quality of life. A gradual approach to exercise is advised, starting with low-impact activities such as swimming or walking, and slowly progressing as tolerated.

There are several proposed mechanisms that explain the therapeutic effects for acupuncture on pain reduction. On the surface level, acupuncture can increase microcirculation, decrease muscle tension, and reduce pressure on nerve roots. There is also evidence of the activation of gamma-aminobutyric acid and serotonin to facilitate its analgesic effects while also downregulating proinflammatory cytokines including high mobility group box 1/ receptor for advanced glycation end products (HMGB1/RAGE) and toll-like receptor 4/ nuclear factor kappa B (TLR4/NF-KB). ^, Radiologic studies have found activation of brain regions related to pain perception including the medial prefrontal cortex, anterior cingulate cortex, and periaqueductal gray in individuals undergoing acupuncture. One of the original proposed mechanisms of acupuncture ties into the gate control theory, in which the stimulation of nonnociceptive fibers inhibits ascending nociceptive signals.

Acupuncture has become increasingly popular in the management for chronic pain conditions. In the twenty-first century, approximately 3 million individuals in the United States alone have utilized this practice, with surveys suggesting an increase of users each calendar year. With its growing popularity, the number of studies surrounding the utility of acupuncture in chronic pain conditions has increased. In a meta-analysis performed in 2020, manual acupuncture and electroacupuncture in combination with standard therapy was found to be superior in pain level reduction for cases of chronic nonspecific low back pain when compared to standard therapy alone. In treating other chronic pain conditions such as fibromyalgia, recent evidence has provided moderate quality evidence of pain reduction in short term follow up but only low-quality evidence for long-term pain reduction. Despite the promising data, there are studies that have demonstrated no significant improvement with acupuncture compared to sham acupuncture control groups. Therefore, providers should exercise caution when utilizing acupuncture as a sole therapeutic treatment modality over standard first-line therapies.

Chiropractic care involves spinal manipulation and other manual techniques to treat musculoskeletal pain, particularly back pain. Chiropractors focus on improving spinal alignment and function, which may reduce pain and enhance mobility. At a physiologic level, the practice affects primary afferent neurons from the paraspinals, which may play a role in the process of mitigating pain perception.

Based on recent statistics from the American Chiropractic Association, there are an estimated 35 million Americans who seek chiropractic care annually. Due to its growing popularity, several studies have been performed to evaluate the benefit that chiropractic care may have for cases of chronic pain. A 2019 meta-analysis that reviewed 47 randomized control trials found moderate quality evidence that chiropractic care provided similar results for the management of chronic low back pain when compared to other recommended therapies in short-term follow-up. In the analysis, it was notable that half of the studies reported transient adverse events, mainly affecting the musculoskeletal system. Given the incidence of adverse events, coupled with evidence suggesting nonsuperiority in pain reduction when compared to first-line active therapies, it may be reasonable to use chiropractic care as an adjunct if first-line therapies fail.

High-velocity low-amplitude (HVLA) maneuvers are a common modality used in the chiropractic and osteopathic world. This practice has been associated with adverse events such as cervical artery dissection, vertebrobasilar insufficiency, and arterial spasm in the cervical region, which can result in stroke. In the lumbar region, adverse events can include worsening pain, fractures, and soft tissue strains. Therefore, it is important for providers to be aware of contraindications for HVLA, which include spinal instability, local infection, malignancy, fractures, osteoporosis, rheumatoid arthritis, Down’s syndrome (especially of cervical region), cauda equina, conus medullaris syndrome, fused spinal joints, and recent surgeries. ^,

Massage therapy, particularly deep tissue massage, can help reduce muscle tension and improve circulation, providing pain relief for conditions like fibromyalgia, back pain, and tension headaches. In a survey performed in 2022, it was shown that 11.1% of American adults utilized some form of massage therapy during that year.

Despite the increase in popularity of massage therapy, the utility of the practice in the management of chronic pain conditions is still ongoing. In a systematic review that assessed studies between 2018 and 2023, there was moderate certainty evidence that massage therapy had benefits in pain reduction for cases of chronic back pain, fibromyalgia, myofascial pain, and postbreast cancer surgery pain when compared to control populations. Notable limitations of the research on massage therapy include a consensus definition of what massage therapy entails. For example, in some studies, acupuncture was considered a form of massage therapy while others classified it as a comparison group. In addition, the lack of long-term follow-up in these studies also limits the ability to assess the utility of massage therapy for long-term management of chronic pain conditions.

There are several types of injections that are used in managing chronic pain when conservative treatments fail. These injections may provide benefit by either reducing inflammation, alleviating nerve pain, or promoting healing and will be discussed later.

Cortisone injections

Cortisone injections are commonly used as intra-articular injections to provide pain relief by reducing inflammation for several musculoskeletal conditions. Corticosteroids deliver their effect by translocating intracellularly to affect gene transcription to inhibit the expression of inflammatory leukocytes. There is also a nongenomic mechanism in which corticosteroids bind to a membrane-bound receptor that inhibits phospholipase A2, decreasing production of inflammatory cytokines. At high concentrations, corticosteroids can also decrease production of B and T cells.

Recognition of adverse effects associated with cortisone injections and having a risk and benefit discussion with patients is important when offering this form of treatment. These potential adverse effects include tendon weakening, which can lead to the progression of tears or even ruptures, skin hypopigmentation and atrophy, accelerated rate of osteoarthritic progression and osseous injury. Systemic side effects can include adrenal suppression or insufficiency, facial flushing, hypertension, hyperglycemia, and osteoporosis. To minimize the incidence of these adverse effects, it is recommended to limit the frequency of these injections to less than 4 times a year, with at least 3 months in between repeating injections.

Contraindications to performing cortisone injection include the presence of active systemic infection, uncontrolled diabetes, fracture at site of injection, or injection of a prosthetic joint. These contraindications are centered on the immunosuppressive properties of steroid injections, which can slow the rate of healing and increase the incidence of infections. ^,

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