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Alternatives to Opioids for Managing Pain

Editor: Bruce M. Vrooman Updated: 4/21/2024 9:08:25 PM


The International Association for the Study of Pain (IASP) recently defined pain as "an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage."[1] Pain is frequently classified as chronic or acute pain. Chronic pain refers to ongoing or recurring pain for >3 months; acute pain has an abrupt onset and a duration of <1 month. Subacute pain is another category sometimes used to characterize pain with an intermediate duration of 1 to 3 months.[2][3] Chronic pain can manifest initially as acute pain, which progresses to a chronic state. Many chronic pain conditions are also associated with intermittent acute flare-ups.

Chronic pain is a widespread health problem, with approximately 100 million people in the United States suffering from chronic pain.[4] About 13% to 50% of adults in the United Kingdom have been estimated to suffer from chronic pain.[5] This leads to a significant economic toll through direct healthcare costs associated with the treatment of chronic pain.[6] The estimated economic burden of lost productivity is in the billions of dollars and much higher than that of diabetes, cardiovascular conditions, or cancer.[7][8] Moreover, chronic pain impacts a patient's life in multiple areas, including activity limitations, lost work productivity, reduced quality of life, mood changes, and impaired social interactions.

The goal of treatment for chronic pain is pain intensity reduction and improving a patient's function and quality of life. Besides efficacy, other issues, including adverse effects, economic factors, and patient preference, should also be considered when selecting a treatment modality. Multimodal management has been recommended for chronic pain consisting of nonopioid medications and nonpharmacologic therapies, including exercises, lifestyle modification, physical therapy, pain psychology, behavioral modalities, cognitive behavioral therapy, myofascial release massage, mindfulness practices, and interventional pain modalities.[9][10][11]

The most commonly used pharmacologic alternatives to opioids begin with acetaminophen and nonsteroidal medications. Frequently, these are initiated in acute postoperative patients and continued as chronic medications. Gabapentin is often added for neuropathic pain as well as the anxiety that presents in patients with chronic pain.[12] Duloxetine, an antidepressant, has been effective for chronic neuropathic pain, typically at doses higher than that used for depression.[13] Naturopathic herbal remedies have been used in some instances to avoid dependence on long-term opioids.[14] Other treatment options include muscle relaxants (eg, methocarbamol), baclofen, cyclobenzaprine, and, less commonly, carisoprodol, which has street value and potential widespread abuse similar to benzodiazepines.[15][16][17][18] Decision-making about medications is best if initiated early in treatment, before the development of opioid dependence. For instance, tramadol, also a controlled substance, is often used in acute pain situations postoperatively; however, though considered a "weaker" opioid, the potential for abuse and dependency still exists, and tramadol is best limited to short-term alleviation of acute pain.[19]

Furthermore, clinicians must continue to reevaluate treatment strategies while caring for patients with chronic pain as treatment response may decrease or pain exacerbates, requiring medication adjustments. For instance, if a short course of corticosteroids is being considered for a patient, holding anti-inflammatory medications and increasing gabapentin or duloxetine dosages may be necessary.[20][21] Consequently, chronic pain management is a process necessitating constant adjustment and evaluation by the treating clinician. Effective pain management requires thoughtful discussion with the individual patient and assessment of their functional and psychosocial performance.


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A biopsychosocial model for evaluating and managing chronic pain involves a thorough initial comprehensive evaluation to determine the underlying pathology and other medical and mental health conditions, previous treatment strategies, psychosocial treatment barriers, and patient expectations described by Cheatle in 2016.[22] Additionally, a patient's functional status, including the performance of activities of daily living, mobility, use of assistance devices, and ability to function independently, should be evaluated during the treatment period and measured at regular intervals to document the efficacy of the treatment. Range of motion of the affected joints and measurements are needed to assess improvement or decline.[23]

Along with the physical assessment of the patient, the biopsychosocial model requires an assessment of the mental health and social issues that could impact the perception of pain. Homelessness, home instability, and food scarcity are all factors that lead to variations in a patient's perception of pain.[24] Family situations may also drastically affect a patient's perception of pain. Environmental conditions, including heat and air conditioning, hot water availability, and indoor plumbing, are frequently taken for granted but are not always available to every patient. If these questions are not asked, the assessment is incomplete. 

Another crucial factor is the patient's mental status. Although a complete mental status exam is not required every visit, assessing the underlying cognitive processes by which the patient functions is prudent. Untreated bipolar disorder, depression, schizoaffective disorders, and uncomplicated anxiety could cause the patient to self-medicate, affecting the patient's pain perception. Family dynamics and genetics can affect the patient's perception of pain. Familial tendency to misuse substances may lower the pain threshold and elevate the patient's perception of pain.[25] Therefore, evaluating the psychological and social factors that impact each patient is critical in determining the most effective treatment modalities for each individual. 

After establishing treatment goals, an individualized multimodal management plan should be devised based on the biopsychosocial evaluation. Clinicians should discuss this management approach, each therapy's expected benefits and risks, and the alternative treatments. The approach determined by shared decision-making may then be initiated.[26] 

Issues of Concern

Long-term use of opioids is associated with significant risks, including overdose and opioid misuse. Furthermore, studies show that opioids are no more effective than alternative treatments for chronic pain management. Therefore, nonopioid and nonpharmacologic therapies are preferred over opioids when treating patients with chronic pain. The primary issues of concern when considering alternatives to opioids for managing pain are to ensure that patients understand the expected benefits and risks of opioids, the alternative treatments available, and the treatment goals that have been established before starting a pain management plan.

Implementing the biopsychosocial approach and shared decision-making helps address these concerns. Evaluating the patient's mental health, living situation, employment status, and social support is also prudent. Insurance status plays a role; many modalities are unavailable to the uninsured.[27][28] Over-the-counter medications may be unaffordable to some populations.[27] The multidisciplinary team must create personalized and accessible treatment plans that are effective and affordable for each patient.


Exercise, physical activity, and physical therapy

Physical activity and exercise can reduce the severity of pain and improve function, quality of life, and mental health. The World Health Organization (WHO) in 2015 defined physical activity as any body movement involving skeletal muscles that leads to energy expenditure. The WHO also referred to exercise as a subset of physical activity that "is planned, structured, repetitive, and aims to improve or maintain one or more components of physical fitness."[28] A review of exercise therapy in chronic low back pain found that this modality reduces pain and improves function in patients with low back pain. No difference in efficacy was noted amongst the different types of therapy.[12] 

A more recent Cochrane review in 2017 found that the evidence evaluating the efficacy of exercise and physical activity in chronic pain is of low quality. The review concluded that these interventions are likely safe and may improve the severity of pain, function, and quality of life.[2] The results of a 2016 Cochrane review found that other physical therapy modalities, such as mirror therapy and graded motor imagery, may improve pain and function in complex regional pain syndrome (CRPS).[13] Mirror therapy and graded motor imagery were also beneficial for phantom limb pain.[14] 

Transcutaneous electric nerve stimulation

Transcutaneous electric nerve stimulation (TENS) uses modifiable, low-voltage, battery-powered electric current to stimulate nerves for therapeutic purposes, including pain reduction. TENS is theorized to ameliorate pain via multimodal mechanisms such as reducing dorsal horn neuron sensitization, increasing gamma-aminobutyric acid and glycine levels, and inhibiting glial cell activation.

The medical literature has been in a state of equipoise for decades about whether TENS has utility in pain management. In 2021, the National Institute of Health and Care Excellence, an internationally renowned British clinical guideline developer, opted against TENS for pain management. This prompted pain researchers to conduct the Meta-TENS meta-analysis and systematic review of more than 380 randomized clinical trials.[29] The latter study, published in 2022, reported on data from more than 24,500 clinical trial participants and concluded that lower pain intensity occurred during or immediately after TENS use when compared with placebo. According to the Grading and Recommendations, Assessment, Development, and Evaluation (GRADE) criteria, the researchers deemed their findings to have moderate certainty.[30] A more recent, smaller meta-analysis (40 trials) of pain intensity and opioid use in the postoperative period found utility for TENS in reducing pain at rest and with coughing, along with statistically significant decreases in morphine requirements, the incidence of postoperative nausea and vomiting, dizziness, and pruritus.[31]


Multiple classes of nonopioid medications are routinely used to treat pain, including over-the-counter and prescribed nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, steroids, antidepressants, anticonvulsants, and topical medications.


NSAIDs are one of the most common treatments for low back pain. This medication group inhibits the cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzymes. COX-1 and COX-2 enzymes play a critical role in the inflammatory cascade, producing prostaglandins. Therefore, NSAIDs reduce inflammation, fever, and pain by inhibiting prostaglandin production. COX-1 produces prostaglandins that play a protective gastrointestinal role by reducing gastric acid secretion, maintaining blood flow to kidneys, and supporting platelet aggregation.[16] Selective NSAIDs inhibit only COX-2 and, compared to nonselective NSAIDs, have a lower risk of gastrointestinal and renal adverse events. However, some of the earlier selective NSAIDs were associated with thromboembolic cardiovascular adverse events.[22][23][24] 

A 2013 meta-analysis found that the risk of cardiovascular events with the use of nonselective NSAIDs such as diclofenac and ibuprofen was similar to that of selective NSAIDs. But among all NSAIDs, naproxen seemed to be safest from a cardiovascular standpoint.[25]

A 2016 Cochrane review of the efficacy of NSAIDs in chronic low back pain found that out of the 13 randomized clinical trials (RCTs) included, the results of 6 found NSAIDs more effective than placebo in reducing pain intensity. However, due to the low level of evidence, no firm conclusions could be drawn.[21] Another 2016 Cochrane review looked at the efficacy of topical NSAIDs in chronic musculoskeletal pain in adults. They concluded that topical diclofenac and ketoprofen improved pain intensity in osteoarthritis significantly. However, evidence of efficacy in other musculoskeletal conditions is limited.[26] 

The results of the SPACE RCT were published in 2018, which compared the efficacy of opioids to that of nonopioid medications on pain-related function in patients with chronic back pain and hip or knee osteoarthritis pain. Nonopioid medications included both NSAIDs and acetaminophen. Opioids were not superior to nonopioids in improving function at 12 months, and thus, results argue against the use of opioids for such conditions.[27]


Acetaminophen is an over-the-counter antipyretic and analgesic. Several mechanisms of action have been suggested, including central serotonergic inhibition. The exact mechanism of action is still uncertain.[28] The results of a 2015 systematic review evaluating the efficacy of acetaminophen in chronic pain found little evidence supporting its use.[29] A more recent systematic review assessing medications used in low back pain found that acetaminophen seemed ineffective for acute low back pain.


Oral corticosteroids are commonly used for the management of acute pain and acute flare-ups of chronic pain conditions. Both direct and indirect mechanisms of action have been described. Corticosteroids directly reduce inflammation by inhibiting the phospholipase A2 enzyme and the production of arachidonic acid. Corticosteroids also indirectly reduce inflammation by attenuating pro-inflammatory and enhancing the expression of anti-inflammatory genes.[31] 

The results of a 2017 systematic review found moderate evidence that systematic corticosteroids do not cause any significant improvement in pain intensity and minimal to no improvement in function when used for radicular low back pain. An RCT compared oral 5-day prednisone to a placebo to treat low back pain in the emergency room and found no significant improvement with steroids.[32]


Serotonin and norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs) are the most common classes of antidepressants used to manage chronic neuropathic pain. These pharmacologic agents augment the descending central inhibition of pain.[33] Apart from treating pain, this medication group can effectively manage concomitant mood and sleep issues as well. The results of a 2020 French systematic review concluded with high-quality evidence that SNRIs and TCAs effectively treat neuropathic pain. The review also demonstrated that duloxetine is more effective than venlafaxine, but close monitoring for adverse effects is recommended when higher doses of TCAs are prescribed. The findings of a 2017 systematic review concluded with moderate evidence that both TCAs and SNRIs were ineffective for managing pain intensity in patients with chronic low back pain.


Gabapentin and pregabalin are the most common antiepileptics used for the treatment of chronic pain. These pharmacologic agents inhibit the α-2-δ subunit of voltage-gated calcium channels, which release nociceptive neurotransmitters.[34] The results of a recent systematic review strongly recommended using gabapentin for neuropathic pain and were backed by high-quality evidence. The same review found weak efficacy of pregabalin in managing neuropathic pain. Evidence for other anticonvulsants was inconclusive. Another systematic review that looked at the efficacy of gabapentin and pregabalin in chronic low back pain could not draw any clear conclusions.[30] A 2017 Cochrane review found that gabapentin at a daily dosage of 1800 mg to 3600 mg can effectively reduce pain intensity in postherpetic neuralgia and diabetic neuropathy.[35]

Topical Medications

The results of a recent systematic review of neuropathic pain treatments provided a weak recommendation for the use of high-dose capsaicin topical patches. They concluded with moderate evidence that the efficacy of topical lidocaine was also weak.


Joint injections

Different medications may be injected into the joint space to reduce inflammation or increase lubrication. Corticosteroids are injected into joints to reduce pain and relieve inflammation within the joint space. Local anesthetics may be injected along with steroids to serve in a diagnostic role, anesthetizing the joint, which helps to confirm the source of pain. On the other hand, hyaluronic acid improves joint lubrication, restoring normal joint fluid properties and indirectly reducing inflammation.[17][32] Injections performed with image guidance, such as ultrasound or fluoroscopy, are more accurate than those performed without guidance, enhancing the efficacy and safety of the procedure.[33] Joint injections commonly include those in the facet, hip, glenohumeral, sacroiliac, and knee joints.

The current evidence supports the use of corticosteroids and hyaluronic acid injections in managing certain types of joint pain over others. In 2019, the Osteoarthritis Research Society International published guidelines based on a meta-analysis for the nonsurgical management of knee, hip, and multi-joint arthritis. These guidelines recommended the use of corticosteroid and hyaluronic acid injections for the management of knee osteoarthritis. However, they did not find these treatments effective in managing osteoarthritis-related pain in other joints.[34] A 2020 systematic review provided insights into the efficacy of facet joint corticosteroid injections, finding them effective in managing lumbar facet-mediated pain compared to cervical facet-related pain.[35]

Peripheral nerve blocks

Peripheral nerve blocks can be used as diagnostic and therapeutic tools in managing chronic pain. Peripheral nerve blocks involve the targeted administration of anesthetic or anti-inflammatory agents near a specific nerve or group of nerves to manage pain. Some commonly performed nerve blocks for chronic pain management are occipital nerve blocks, intercostal nerve blocks, medial branch nerve blocks, and genicular nerve blocks.[36]

Despite their utility, a 2020 French systematic review highlighted the inconclusive evidence regarding the efficacy of nerve blocks in managing neuropathic pain, particularly noting gaps in long-term pain relief and effectiveness across different types of neuropathic conditions. This calls for more targeted research to ascertain their effectiveness, especially concerning long-term outcomes and specific neuropathic pain syndromes.[37] 

Trigger point injections

Trigger point injections are a therapeutic option for the treatment of myofascial pain syndrome. These injections involve delivering a local anesthetic, with or without corticosteroids, directly into the muscle's trigger points. The local anesthetic works to anesthetize the area, while corticosteroids reduce inflammation. The relaxation of muscle fibers is achieved through vasodilation induced by the injectate, coupled with the mechanical disruption of the myofascial trigger points by needle insertion. This dual mechanism helps alleviate pain and restore muscle function.[38]

While trigger point injections are generally considered safe, they are not without risks. Serious adverse events, such as pneumothorax and inadvertent intravascular and intrathecal injections, have been reported. Using ultrasound guidance during trigger point injections can significantly enhance the safety and efficacy of the procedure. Ultrasound allows for real-time visualization of the needle's path, ensuring accurate placement in the targeted muscle and minimizing the risk of adverse events. By reducing the likelihood of puncturing unintended structures, ultrasound guidance helps make trigger point injections a safer and more effective treatment option for myofascial pain.[39][40]

Epidural steroid injections

Epidural steroid injections are a widely utilized intervention for managing spine-based pain by reducing local inflammation in the epidural space.[41] The results of several studies show the effectiveness of epidural steroid injection for the short-term treatment of specific pain processes, but the long-term data is inconclusive.   

In 2015, a systematic review supported the use of cervical epidural injections of local anesthetic with or without steroids for the treatment of neck and arm pain.[42] The results of a 2016 meta-analysis demonstrated that the injection of lidocaine, with or without steroids, was effective in treating conditions such as lumbar radiculopathy and spinal stenosis.[43] Further supporting their efficacy, a 2017 meta-analysis found similar findings for epidural injections in treating radicular low back pain.[44] 

While epidural steroid injections are a cornerstone in the nonoperative management of spinal pain, clinicians need to consider potential limitations and safety concerns. Complications, though rare, can include infection, bleeding, and, in some cases, worsening pain.

Radiofrequency ablation

Radiofrequency ablation uses short bursts of high-frequency current applied to nerve tissue in a minimally invasive neuroablative technique for pain management. In recent years, radiofrequency ablation has been studied extensively, with positive results for pain reduction or control in coccydynia, sacroiliac pain, knee osteoarthritis, and postherpetic neuralgia.[45][46][47][48][49][50] Radiofrequency ablation is one of the few techniques with efficacy in thoracic and abdominal pain, otherwise notoriously refractory to conservative measures.[51] However, the utility in Morton neuroma has not been established, necessitating additional RCTs in this condition.[52] 

Sympathetic nerve blocks

Sympathetic nerve blocks are crucial in managing CRPS, which is characterized by chronic, severe pain and sympathetic nervous system hyperactivity.[53] Lumbar sympathetic nerve blocks are utilized to treat lower extremity pain, while stellate ganglion blocks are used to treat arm pain.

The evidence for the treatment of CPRS with sympathetic nerve blocks is mixed. The results of a 2023 Cochrane review indicated that these nerve blocks may not significantly reduce pain intensity. Earlier results in Cochrane reviews in 2013 and 2016 reported mixed outcomes, suggesting some potential benefits. However, sympathetic nerve blocks continue to be utilized as one of the initial treatments for CRPS. This approach aims to slow the disease's progression and mitigate the risk of long-term disability.[54]

Spinal cord stimulation

Spinal cord stimulation was first used, with good, nearly immediate effect—in an n-of-1 clinical trial setting—more than 50 years ago.[55] This pioneering work in bioelectric medicine set the stage for developing spinal cord stimulation as a nonpharmacologic pain reduction intervention and the eventual development of targeted neuromodulation more generally.[56] Comprising a small, pacemaker-like battery implanted under the skin near the abdomen or buttocks connected by thin wires to electrodes placed into the epidural space (also known as the dorsal column) between the vertebrae and the spinal cord itself, the spinal cord stimulator is triggered by the patient to send electrical impulses to the spinal cord when pain is felt. Traditionally, spinal cord stimulators replace pain with tingling (paresthesia), which some patients find uncomfortable. In recent years, high-frequency stimulation with 10 kHz waveforms has partially supplanted traditional spinal cord stimulation. Trial results, both prospectively and retrospectively, have shown more than 50% pain relief in more than 70% of treated patients; results were sustained for at least 1 year and were accompanied by salubrious reductions in the mean daily dose of opioids required by patients. High-frequency stimulation also benefits diabetic peripheral neuropathy, when otherwise refractory to intervention, and long-term improvement in health-related quality of life.[57] Dorsal root ganglion stimulation permits more targeted delivery of stimulation and is a newer treatment modality. A pooled analysis study concluded that dorsal root ganglion stimulation is safe and effective for multiple chronic pain problems, including failed back surgery syndrome and CRPS.[56]

Behavioral therapy

Chronic pain can be associated with maladaptive or negative thinking and behavior related to painful stimuli. Cognitive-behavioral therapy reduces maladaptive thinking and facilitates the development of pain-related coping skills and overall improved functioning while reducing pain intensity in patients with chronic pain.[59][16] 

Clinical Significance

Opioids increase the risk of addiction and overdose. The United States is currently in the midst of an opioid epidemic. Moreover, limited evidence supports the use of long-term opioid use for managing chronic pain. The list of nonopioid treatments for pain is extensive, including nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, corticosteroids, antidepressants, anticonvulsants, and topical medications. Other treatment modalities include physical therapy, chiropractic, acupuncture, TENS, cognitive behavioral therapy, myofascial release massage, and mindfulness practices. Interventional pain management procedures include peripheral nerve blocks, joint injections, trigger point injections, epidural steroid injections, and radiofrequency ablations. More invasive neuromodulation procedures such as spinal cord, dorsal root ganglion, and peripheral nerve stimulator therapy can also be considered for intractable pain.

Not all patients are candidates for every available nonopioid pain therapy. A patient's interprofessional care team should know the vast array of available nonopioid treatment options and understand each modality's mechanism of action, indications, and associated complications. The level of existing evidence in support of efficacy should also be considered. When making a treatment decision, existing medical and psychiatric comorbidities and patient preferences should also be considered. A biopsychosocial model has been recommended for designing an individualized multimodal treatment plan. Early consultation with pain specialists should be considered when treating patients with chronic pain for optimal outcomes.[58][59]

Enhancing Healthcare Team Outcomes

Under the biopsychosocial care model, interprofessional care is important in patients with chronic pain using alternative treatments to opioids. Optimal care can only be provided through a combined team approach involving physicians, nurses, physical therapists, occupational therapists, psychologists, pharmacists, and social workers. The treating clinician's role includes integrating all affiliated team members, whether nurses, pharmacists, or social workers. While the role of the prescribing clinicians is to make pharmacologic decisions, the plan must also encompass input from the entire interprofessional team. By working as a team, the patient can be assured of a coordinated approach to restore function and minimize discomfort. In this way, the patient is assured that their treatment goals and preferences are valued and respected.[14][60] This united approach supports the patient's progress and helps prevent the risks associated with opioid medications.[61]



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