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Alternatives to Opioids for Managing Pain

Editor: Bruce M. Vrooman Updated: 7/21/2023 11:20:53 PM


The International Association for the Study of Pain (IASP) revised the definition of pain in 2020 as "An unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage." [1] Ongoing or recurring pain for three or more months has been defined as chronic pain by the same organization.[2]  In comparison, acute pain can have an abrupt onset and is usually short-lasting.[3] Chronic pain problems usually manifest initially as acute pain, and many chronic pain conditions are associated with an intermittent acute flare-up of pain.[4]

Chronic pain is a widespread health problem, with approximately 100 million people in the United States suffering from chronic pain in 2008.[5] About 13 to 50% of adults in the United Kingdom have been estimated to suffer from chronic pain.[6] This leads to a significant economic toll through direct healthcare costs associated with treatment and lost productivity. The estimated economic burden ranged from $560 to $635 billion in 2010, which is much higher than that of diabetes, cardiac problems, or cancer.[5]

The goal of treatment for chronic pain is the reduction of pain intensity and the improvement of function and quality of life. Apart from efficacy, the adverse effects, side-effect profile, economic factors, and patient preference should also be considered during the selection of a treatment modality. Multimodal management has been recommended for chronic pain, including medications, exercises, lifestyle modification, physical therapy, pain psychology, behavioral modalities, interventional pain modalities, and alternative medicine.[7]


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A biopsychosocial model for evaluation and management of chronic pain was described by Cheatle in 2016.[8] This approach involves a thorough initial comprehensive evaluation to determine not only the patient’s underlying pain pathology but also other medical and mental health problems, previously trialed treatment strategies, psychosocial treatment barriers, and patient expectations. An individualized multimodal treatment plan should be instituted based on the evaluation, and patients should be educated about the approach after establishing treatment goals.

Issues of Concern

The United States is currently in the midst of an opioid epidemic with increased opioid use over the last two decades. In 2016, prescription opioid misuse was found in at least 4% of the United States adult population.[9] More than 33,000 people died due to opioid overdoses in 2015, both prescribed and illicit.[10] Apart from the risk of overdose and addiction, there is limited evidence supporting the efficacy of long-term opioid therapy in chronic pain. Therefore, in 2016 the Centers for Disease Control and Prevention (CDC) published guidelines for prescribing opioids in non-cancer, non-palliative chronic pain conditions. The guidelines endorse a preference for non-opioid treatments for managing chronic pain.[11] This article aims to review such alternative non-opioid treatment options.


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. World Health Organization (WHO) in 2015 defined physical activity as any body movement involving skeletal muscles that leads to energy expenditure. Whereas exercise was referred to, by WHO, as a subset of physical activity that “is planned, structured, repetitive, and aims to improve or maintain one or more components of physical fitness.”[2]  A review of exercise therapy in chronic low back pain found that this modality reduces pain and improves function in patients suffering from 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 body of 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] A 2016 Cochrane review found that other physical therapy modalities such as mirror therapy and graded motor imagery (GMI) may improve pain as well as function in complex regional pain syndrome (CRPS).[13] Mirror therapy and GMI were found to be beneficial for phantom limb pain as well.[14] 

Transcutaneous Electric Nerve Stimulation (TENS)

Transcutaneous electric nerve stimulation (TENS) involves the application of adhesive skin surface electrodes to the painful area. TENS uses modifiable low-voltage electric currents, which are usually powered by a battery. This modality has been used to treat multiple pain problems. A central as well as a peripheral mechanism of action has been proposed.[15] The gate theory of pain described by Melzack in 1965 serves as the most widely accepted central mechanism of action. TENS stimulation likely activates the large fiber Aβ afferent neurons, which in turn inhibit nociceptive transmission at the dorsal horn of the spinal cord.[16] 

A 2017 Cochrane review studied the efficacy of TENS therapy in neuropathic pain but was not able to make any firm conclusions due to a very low level of evidence.[15] A more recent 2020 systematic review made a weak recommendation for the use of TENS in neuropathic pain based on the moderate quality of evidence.[17] Another Cochrane review was targeted at the efficacy of TENS in fibromyalgia, but due to the low quality of evidence, no definitive conclusions could be drawn.[18] A Cochrane database review of TENS efficacy in adult cancer pain was also inconclusive.[19] A 2019 systematic review of the efficacy of TENS in chronic neck pain was inconclusive as well.[20]


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


NSAIDs are one of the most common treatments for low back pain.[21] 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 leading to the production of prostaglandins. Therefore, NSAIDs reduce inflammation, fever, and pain by inhibiting prostaglandin production. COX-1 is involved in the production of 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 non-selective NSAIDs, have a lower risk of gastrointestinal and renal adverse events.[21] But some of the earlier selective NSAIDs were found to be associated with thromboembolic cardiovascular adverse events.[22][23][24] 

A 2013 metanalysis found that the risk of cardiovascular events with the use of non-selective 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, 6 found NSAIDs to be more effective than placebo in reducing pain intensity. But 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 both topical diclofenac and ketoprofen seemed to deliver significant improvement in pain intensity in osteoarthritis. 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 non-opioid medications on pain-related function in subjects suffering from chronic back pain, hip or knee osteoarthritis pain. Non-opioid medications included both NSAIDs and acetaminophen. Opioids were not found to be superior to non-opioids 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. But the exact mechanism of action is still uncertain.[28] A systematic review published in 2015 evaluating the efficacy of acetaminophen in chronic pain found little evidence supporting its use.[29] A more recent systematic review evaluating medications used in low back pain found that acetaminophen seemed ineffective for acute low back pain.[30]


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 reduce inflammation indirectly by attenuation of pro-inflammatory and enhance expression of anti-inflammatory genes.[31] 

A 2017 systematic review found with a moderate level of 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.[30] An RCT compared oral 5-day prednisone to 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 descending central inhibition of pain.[33] Apart from treating pain, this medication group can effectively manage concomitant mood and sleep issues as well. A 2020 French systematic review concluded with high-quality evidence that both SNRIs and TCAs were effective in treating neuropathic pain.  The review also found duloxetine to be more effective than venlafaxine but recommended close monitoring for side effects when higher doses of TCAs are used.[17] A 2017 systematic review concluded with a moderate level of evidence that both TCAs and SNRIs were ineffective for managing pain intensity in chronic low back pain.[30]


Gabapentin and pregabalin are the most common antiepileptics used for the treatment of chronic pain. These pharmacologic agents inhibit the alpha-2-delta subunit of voltage-gated calcium channels, which are involved in releasing nociceptive neurotransmitters.[34] A recent systematic review strongly recommended using gabapentin for neuropathic pain and was backed by high-quality evidence. The same review found weak efficacy of pregabalin in managing neuropathic pain. Evidence for other anticonvulsants was found to be inconclusive.[17] 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 to 3600 mg can effectively reduce pain intensity in postherpetic neuralgia and diabetic neuropathy.[35]

Topical Medications

A recent systematic review of neuropathic pain treatments gave a weak recommendation for the use of high-dose capsaicin topical patch. They concluded with moderate quality of evidence that the efficacy of topical lidocaine was also weak.[17]


Joint Injections

Corticosteroids are injected into joints to reduce inflammation-related pain.[36] Local anesthetic injected along with steroids in the joints can serve a diagnostic role as well. Injections performed with image guidance are much more accurate than those performed without guidance.[37] Commonly performed joint injections include facet, hip, glenohumeral, sacroiliac, and knee joint injections. Apart from the injection of corticosteroids, hyaluronic acid has also been extensively used for the reduction of pain and improvement of function in knee osteoarthritis.[36] 

In 2019, the Osteoarthritis Research Society International (OARSI) published guidelines based on a metanalysis for non-surgical management of knee, hip, and multi-joint arthritis. They made a Level 1B/2 recommendation for the use of both corticosteroid and hyaluronic acid knee joint injections for the management of knee osteoarthritis but did not find them effective in the treatment of osteoarthritis-related pain in other joints.[38] A 2015 systematic review found that facet joint steroid injections are more effective in managing low back pain compared to neck pain. They found Level 3 evidence supporting the use of corticosteroid joint injections for long-term reduction of pain related to lumbar facet mediated pain and level 4 evidence for cervical facet related pain.[39]

Peripheral Nerve Blocks

Peripheral nerve blocks can be used as both diagnostic and therapeutic agents in the management of chronic pain.[40] Occipital nerve blocks, intercostal nerve blocks, medial branch nerve blocks, and genicular nerve blocks are a few commonly performed nerve blocks. Despite their widespread use, a 2020 French systematic review found that evidence of the efficacy of nerve blocks in managing neuropathic pain was inconclusive. [17] More studies are required to evaluate efficacy. 

Trigger Point Injections

Trigger point injections may be used for the treatment of myofascial pain syndrome.[41] These injections involve the intramuscular injection of local anesthetic with or without steroids. Relaxation of muscle fibers as a result of vasodilation caused by injectate and disruption of the myofascial trigger points by needle insertion are the proposed mechanisms of action. These injections are generally safe, but a few serious adverse events such as pneumothorax, intravascular and intrathecal injections have been reported. But, using ultrasound guidance to perform trigger point injections can prevent such complications and render them more effective.[42]

Epidural Steroid Injections

Epidural steroid injection is the commonest intervention performed for spine-based pain.[43] Injection of steroids in the epidural space reduces local inflammation. A 2016 metanalysis found that injection of lidocaine with or without steroids in the epidural space was effective in treating lumbar radiculopathy and spinal stenosis.[44] Another 2017 metanalysis found similar results in radicular low back pain.[45] For managing neck and arm pain, a systematic review found level 2 evidence supporting the use of cervical epidural injection of local anesthetic alone or in combination with steroids.[46]

Radiofrequency Ablations

Radiofrequency ablation is a denervation procedure that involves the thermocoagulation of nerves.[47] A systematic review found Level 2 evidence supporting the use of radiofrequency ablations of medial branch nerves for long-term reduction of facet mediated cervical and lumbar spine pain. But for thoracic radiofrequency ablations, the level of evidence was much lower at level 4.[39] Radiofrequency ablation of sacral lateral branches can effectively reduce sacroiliac joint mediated pain, but there is limited evidence supporting the use of this treatment.[48] Radiofrequency ablation of genicular nerves was also found to be effective in the management of pain related to knee osteoarthritis by a 2019 review.[49] 

Sympathetic Nerve Blocks

Sympathetic nerve blocks (SNBs) are routinely used in the treatment of complex regional pain syndrome (CRPS), where sympathetic hyperactivity is an underlying pathophysiologic mechanism.[50] For lower extremity pain, lumbar sympathetic nerve blocks are performed, whereas stellate ganglion blocks are performed to treat arm pain symptoms. A 2013 Cochrane review found a low level of evidence supporting the use of SNBs in CRPS, but a more recent Cochrane review was inconclusive.[51][52] Despite the weak evidence, SNBs are one of the earliest interventions performed in CRPS to slow progression and prevent long-term disability associated with this disorder. SNBs have also been used to treat chronic pelvic and perineal pain.[53]

Spinal Cord Stimulation

In spinal cord stimulation (SCS) therapy, electrodes are placed in the spine to stimulate the dorsal aspect of the spinal cord. The electrodes are then connected to an implanted pulse generator, but some devices use an external pulse generator. The pulse generator serves as the power source for the electrodes. Reversal of cortical neuroplastic changes, attenuation of spinal cord nociception, vasodilation, and adrenergic inhibition are a few of the proposed mechanisms of action of SCS.[50] A systematic review published in 2016 found a high level of evidence supporting the use of SCS in lumbar failed back surgery syndrome.[54] Another 2017 systematic review also found a high level of evidence to support SCS use in CRPS.[55] But a recent systematic review made a weak recommendation for the use of SCS in neuropathic pain related to failed back surgery syndrome and diabetic neuropathy based on the moderate quality of evidence.[17] Despite this recent review focusing only on neuropathic pain, SCS therapy is a viable treatment option for intractable pain not amenable to any other surgical treatment.  

Dorsal Root Ganglion and Peripheral Nerve Stimulation

Dorsal root ganglion (DRG) stimulation allows for even more targeted delivery of stimulation and is a newer treatment modality. A pooled analysis study concluded that DRG stimulation is safe and effective for multiple chronic pain problems, including FBSS and CRPS.[56] The ACCURATE multicenter study found that for CRPS, DRG stimulation was more effective than SCS.[57] Peripheral nerve stimulation involves the placement of stimulation electrodes in the proximity of affected peripheral nerves. The electrodes can be connected to an implanted rechargeable battery or an external power source. This treatment modality reduces pain through both central and peripheral mechanisms.[58] A 2020 French systematic review found that evidence was inconclusive for the efficacy of peripheral nerve and DRG stimulation in treating neuropathic pain.[17] Clearly, more research is needed to establish the long-term efficacy of these new novel pain treatment modalities.  

Behavioral Therapy

Chronic pain can be associated with maladaptive or negative thinking and behavior related to painful stimuli. Cognitive-behavioral therapy (CBT) reduces such catastrophizing and maladaptive thinking. CBT leads to the development of pain coping skills and overall improved functioning.[16] CBT can also reduce pain intensity in chronic pain patients.[59]

Clinical Significance

Opioids increase the risk of addiction and overdose. The United States is currently in the midst of an opioid epidemic. Moreover, there is limited evidence supporting the use of long-term opioid use for managing chronic pain. The list of non-opioid treatments for pain is extensive. It includes medications such as NSAIDs, acetaminophen, corticosteroids, antidepressants, anticonvulsants, and topical medications. Physical therapy, chiropractic therapy, acupuncture, TENS unit, and behavioral therapy are other treatment modalities. 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 SCS therapy, DRG, and peripheral nerve stimulation can also be considered for intractable pain.

However, each patient is not a candidate for every available non-opioid pain therapy. The care team of a patient should be aware of the vast array of available non-opioid treatment options and have a basic understanding of the mechanism of action, indications, and associated complications of the modalities. 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 taken into account. A biopsychosocial model has been recommended for designing an individualized multimodal treatment plan. Pain clinic consultations should be considered early in the care of chronic pain patients to aid in optimal treatment selection.

Enhancing Healthcare Team Outcomes

Under the biopsychosocial care model, interprofessional care is needed to provide comprehensive care to chronic pain patients. Optimal care can only be provided through a combined team approach involving physicians, nurses, physical therapists, occupational therapists, psychologists, and social workers.



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