Utilizing Non-Opioids for Chronic Pain in the Setting of an Opioid Epidemic


March 1, 2017


March 31, 2019


Aimee L. Dietle, PharmD
Assistant Professor of Pharmacy Practice
MCPHS University
Worcester, Massachusetts

Marisa C. Campanale, PharmD
Clinical Pharmacist
Holyoke Health Center, Inc.
Holyoke, Massachusetts

Jerril Varghese, PharmD
PGY1 Community-Based Pharmacy Resident
Holyoke Health Center, Inc.
Holyoke, Massachusetts


Drs. Dietle, Campanale, and Varghese have no actual or potential conflicts of interest in relation to this activity.

Postgraduate Healthcare Education, LLC does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous. Occasionally, authors may express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective analysis of scientific data.


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Credits: 2. 0 hours (0. 20 ceu)
Type of Activity: Knowledge


This accredited activity is targeted to pharmacists. Estimated time to complete this activity is 120 minutes.

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Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients' conditions and possible contraindications or dangers in use, review of any applicable manufacturer's product information, and comparison with recommendations of other authorities.


To educate pharmacists about the challenges associated with treating chronic pain and the safety and efficacy of alternative therapy options in relation to opioids.


After completing this activity, the participant should be able to:

  1. Describe the challenges associated with pharmacologic treatment of chronic pain.
  2. Identify non-opioid therapies that can substitute for opioids when it comes to treating chronic pain.
  3. Compare and contrast the clinical efficacy and safety profiles of alternative therapies for chronic pain management.
  4. Recognize the role of the pharmacist in reducing pain.

ABSTRACT: Chronic pain is often difficult to treat because of its subjective nature and complex pathophysiology. Opioids are increasingly prescribed to treat chronic pain. The growing nature of the opioid epidemic is causing clinicians to seek out alternative therapies. There is limited evidence that opioids provide any long-term benefit in chronic pain conditions, whereas the risks of abuse, diversion, and overdose are evident. Alternative therapies for chronic pain include acetaminophen, NSAIDs, anticonvulsants, and antidepressants such as SNRIs and TCAs. Clinicians should strive to utilize these alternative therapies in place of, or in addition to, opioid therapy for chronic pain.

Chronic pain is defined by the CDC as persistent pain that lasts >3 months or past the time of normal tissue healing. 1 Chronic pain is associated with high direct and indirect costs from the medical expenses involved with diagnosis, treatment, and follow-up, and the expenses incurred from missed work and immobility. 2 Additionally, chronic pain places a large burden on a patient’s quality of life and is often associated with high rates of depression and anxiety. 2 These accompanying conditions impose their own expenses and challenges on the patient and can create a vicious cycle. In addition to the burdens and costs of chronic pain itself, the treatment of this disease has proved challenging. Clinicians have long been relying on the use of opioids for the treatment of both acute and chronic pain.

The United States now finds itself in an opioid epidemic that it has never seen before. 3 It is becoming increasingly important to recognize the potential risk of abuse and addiction with chronic opioid use. Clinicians need to balance the risks and benefits of opioid use in a patientspecific manner. This lesson synthesizes available evidence to provide guidance for clinicians who are weighing the use of non-opioids versus opioids for the treatment of chronic pain.


Among chronic disease states, chronic pain continues to have one of the highest incidence rates. 4 It also ranks high on the list of leading reasons individuals seek healthcare in the U. S. 4 Over the past decade, prescriptions for opioids continued to rise while the rate of use of nonopioid therapies has stayed relatively the same. 5 In 2012 alone, 259 million prescriptions for opioids were written. 6

In order to understand the varied reasons behind these statistics, as well as the challenges of treating chronic pain, it is important to examine the physiology of pain and identify the core targets that, when treated appropriately, can reduce the burden of pain.

Physiology of Pain

Treating pain is often difficult because of its highly subjective nature. Pain processes are also dynamic; in other words, pain can change and does not remain static. 7

There are different types of pain, which, if not properly assessed, could lead to difficulties in finding an effective treatment option. The most common types of pain can be classified into two general groups: nociceptive pain (somatic and visceral) and neuropathic pain. 8

Nociceptive Pain: The pain that signals tissue damage is nociceptive pain. This occurs by stimulation of nociceptors—sensory nerve cells responsible for detecting damage to surrounding tissues. Substances that can activate nociceptors include bradykinin, histamine, prostaglandins, substance P, and other molecules associated with tissue injury. 7 The ascending sensory nerves of nociceptors are made up of two types of fibers: A-delta fibers and C fibers. 9 One difference between both types of nerve fibers is that A-delta fibers are myelinated, while C fibers are unmyelinated. The result is a difference in the speed of sensory-information relay. 7,9 This is why some pains are dull, achy, and prolonged, while others are sharp, stinging, and quick. For example, when a person stubs his or her toe on a door, the immediate pain that is perceived is a result of sensory information traveling through the A-delta fibers. The dull and achy pain that comes afterward is a result of the C fibers. 9 Nociceptive pain is described by tissue or organ-related pain and often responds to acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), and opioids. 10

Neuropathic Pain: Burning, throbbing, nerve-related pain is known as neuropathic pain and often responds to antidepressants and anticonvulsants. 10 Neuropathic pain occurs as a result of damage to sensory fibers. 7,9 Often, this can be secondary to another disease or injury. 7 Unlike nociceptive pain, resolving the disease or injury may not alleviate neuropathic pain. The damage to the nerve fibers can result in random generation of conduction signals. 7 This is analogous to a power line that is damaged; it can create sparks or discharge at any given time. Similarly, sensory fibers that are damaged in the body can generate signals that will be perceived as pain even in the absence of tissue damage. Studies have shown that patients living with neuropathic pain demonstrate higher pain scores and have rated their quality of life in regard to their health lower than patients who are experiencing non-neuropathic pain. 11

While pain signals are relayed from the peripheral areas to the central nervous system (CNS), there is also information that travels back down from the brain via the descending fibers. 12 The descending fibers are known for their role in modulating pain. 12 They release hormones that modulate pain signals and are key targets when it comes to blocking pain sensation. 12

One of these substances, endorphins, can act like “endogenous morphine” by targeting mu-opioid receptors on presynaptic sensory cells. 13 Endorphins exhibit their effect by blocking pain transduction. 13 Therefore, a simple means to pain control would seem to be a therapeutic drug that targets and agonizes the muopioid receptor. Opioids are the drugs of choice for targeting mu-receptors. Unfortunately, mu-receptors are also present in the CNS, where activation can inhibit the release of gamma-aminobutyric acid and increase the levels of dopamine. 14 A flood of dopamine in the brain can cause euphoria in the reward center of the brain and may play a role in the prevalence of addiction and dependence associated with opioid therapy. 14 While opioids are easy choices for therapy, pain can also be modulated via other pathways.

A Stepwise Approach

Guidelines and evidence for effective treatment options for chronic pain can vary depending on the diagnosis. Clinicians are encouraged to determine the root cause and treat accordingly. The World Health Organization’s stepwise approach for treating pain has been widely adopted and many treatment guidelines are modeled after this approach. 15 The first step is to begin with non-opioid analgesics, specifically acetaminophen and NSAIDs. 15 The next step is to progress to lower-dose/ lower-potency opioids. 15 The third step is to move to higher-dose/stronger-potency opioids. 15 Other adjuvant therapies like antidepressants and anticonvulsants (TABLE 1) are considered at each step. 15

This stepwise approach to treatment is beneficial in ensuring that non-opioids are used first, but has also led to an increase in opioid prescribing, as many patients may not respond to the first step. 15 Due to the subjective nature of pain and the challenges of its assessment and treatment, it is important that patients be educated in a meaningful way on how to use pain scales or other treatment-evaluation tools, and on the goals of therapy. 1 In this way, if it is concluded that a treatment has failed, it is truly a treatment failure and not due to a misunderstanding of treatment expectations.



Opioids as a class are currently considered to be one of the most effective treatments for acute pain. There is no dose ceiling, leading clinicians to be able to continue to titrate until analgesic effect is reached or adverse events become intolerable. In contrast, their effectiveness for chronic pain has yet to be explored.

According to the 2016 CDC guidelines for prescribing opioids for chronic pain, there are no long-term studies meeting CDC standards that compare the effectiveness of opioids to that of non-opioids or placebo for chronic pain. 1 What is known is that physiologic tolerance to opioids can develop, requiring escalating doses with chronic use. These escalated doses (especially ≥50 mg of morphine equivalents) and longer-term use of opioids are associated with significant risks, such as opioid-use disorder, overdose, myocardial infarction, motor vehicle injury, and even death. 1 Total daily doses ≥90 mg of morphine equivalents should be avoided or used only with extreme care by a specialist. 1 The 2016 CDC guidelines provide evidence that chronic use of opioids may be linked to increased opioid abuse and dependence. In addition, a higher dose of opioid therapy is associated with higher incidences of overdose. 1

Opioids have adverse events ranging from constipation to CNS and respiratory depression. 15 Adverse events are a particular concern in elderly patients, who commonly experience chronic pain requiring pharmacologic treatment. 15 In addition to the adverse events previously described, opioids carry additional risks in elderly patients, including increased rates of falls, fractures, and hospitalizations. 15 Due to 1) the documented adverse risks of opioids, 2) the setting of an unprecedented opioid epidemic in the U. S. , and 3) no quality evidence of benefit with chronic use, clinicians should be increasingly vigilant with regard to opioid use and utilize non-opioid analgesics when possible for treatment of chronic pain. 1,3

Opioids should be initiated only after all other options are exhausted. If opioids must be used, nonopioid analgesics should be used as adjuvant therapy in an attempt to reduce the amount of opioid utilized. 1

The clinician and patient must engage in discussion of the risks and benefits of opioid therapy, including the risk for dependence. 16 If the benefits outweigh the risks, realistic goals of therapy and a pain-treatment contract must be established between the clinician and the patient. 6,16 The patient should be followed continuously and be monitored for analgesia, adverse events, and changes in behavior. 16


Acetaminophen is typically considered first-line therapy for chronic pain conditions, including osteoarthritis (OA) and chronic pain associated with total knee arthroplasty. 2,10 However, many times patients are treated inappropriately with opioids instead. 2 Acetaminophen is considered first-line treatment for many pain conditions because of its safety advantages. Compared with other analgesics available, acetaminophen is associated with very few adverse events and is considered safe to use chronically. 10 Healthcare providers strive to “first do no harm. ” Therefore, for most chronic pain conditions, a trial of acetaminophen should be used and monitored for effect before initiating other analgesics, including opioids.

However, acetaminophen is not without risks. Safety concerns associated with acetaminophen include serious liver damage if ingestion is greater than the recommended total daily dose of 4,000 mg. 15 Long-term high doses of acetaminophen and accidental overdose from inadvertently consuming multiple acetaminophen products are the leading causes of acute liver failure in the U. S. 8,15

For this reason it is important that the patients who are utilizing acetaminophen chronically for pain are educated on proper dosing and administration, and are aware of any other acetaminophen-containing products they may use. The disadvantage of acetaminophen is that it often cannot provide a sufficient analgesic effect and does not exert a specific anti-inflammatory effect, causing many patients to discontinue or switch therapies. 2,11


The main pharmacologic outcomes of NSAIDs include anti-inflammatory, analgesic, and antipyretic effects. 11 The benefits of NSAIDs may not always outweigh the risks, as they have been associated with many and severe adverse events in the cardiovascular, gastrointestinal (GI), and renal systems. 15 When compared with NSAIDs, opioids may be more effective and even preferred for short-term analgesia, but for chronic pain, both safety and efficacy need to be explored. 10 Two separate double-blind, double-dummy studies compared the reduction in pain in adults who had low back pain treated with tramadol 50 mg four times daily versus celecoxib 200 mg twice daily. The results showed a greater response to celecoxib use. 17 Based on Cochrane reviews, opioids (including morphine and oxycodone) did not show superiority over NSAIDs when used for treating chronic low back pain. 18 Therefore, NSAIDs could be considered an effective alternative to opioids in this population.

Although NSAIDs have been shown to be efficacious, their adverse event profile in the setting of chronic use should be thoroughly considered. NSAIDs have recently come under scrutiny by the FDA regarding their risk of increasing cardiovascular events. 19 NSAIDs have been associated with increased risk of fluid retention or the worsening of it, hypertension, congestive heart failure, myocardial infarctions, and cerebrovascular events. 15,19

Due to this risk, chronic use of NSAIDs should be avoided in patients with significant ischemic heart disease or cerebrovascular disease. 10 When NSAIDs are warranted for patients at high cardiovascular risk, either naproxen or celecoxib may be preferred, although this evidence is debated. 8,19,20

NSAIDs also pose risks for adverse GI events. When NSAID treatment is chosen, it is recommended to use the lowest effective dose available for the shortest duration of therapy. 10

Patients who may be at risk for GI adverse effects from NSAIDs include those with a history of ulcers, concurrent use of another NSAID; anticoagulants, or corticosteroids; those who require a high dose of an NSAID; and those who are older than 75 years. 21 These patients may benefit from co-administration of a protonpump inhibitor or histamine-2 receptor agonist along with an NSAID (a selective cyclooxygenase inhibitor agent may be preferred). 10,20,21

The effects on the renal system should also be considered for any patients with or at high risk for renal insufficiency. NSAIDs have been associated with water or sodium retention or the worsening of it, decreased renal blood flow, electrolyte imbalances, and both acute and chronic renal failure. 15 Repeated use of NSAIDs should be avoided in anyone with chronic renal insufficiencies.

Chronic use of both NSAIDs and opioids is associated with increased adverse events, so the decision to use one rather than the other for chronic pain needs to be individualized in a patient-centered approach. The increased risk of GI and cardiovascular events should be weighed against the increased risk of addiction and accidental overdose from opioids. NSAIDs, when used in low-cardiovascular-risk patients with proper GI prophylaxis, may be an effective alternative compared with opioids for chronic pain. Topical NSAIDs can also be considered for those at high risk for adverse events, such as elderly patients, and have been shown to be effective in chronic pain conditions like OA. 10, 15

Topical Products

Topical products are often overlooked when it comes to treating chronic pain. Topical products can be beneficial to patients who are unable to tolerate, or are at risk for adverse events from, oral medications. 22 Topical products to consider for chronic pain include topical anesthetics and topical NSAIDs. According to a 2016 review in the Journal of Pain and Symptom Management, lidocaine 5% and capsaicin 8% patches were compared against oral pregabalin and showed evidence for pain relief in the setting of peripheral neuropathic pain. 22 While lidocaine did not meet the predefined criteria for noninferiority, it did show similar levels of pain relief when compared with pregabalin. 22 Capsaicin was able to demonstrate noninferiority. 23,24 Another study, published in January 2017, was a double-blind, placebo-controlled trial that compared capsaicin 8% to placebo in patients with painful diabetic neuropathy. 24 The results confirmed the clinical use of capsaicin as an effective choice for pain relief. 24

In a 2016 update to a Cochrane review of the use of topical NSAIDs for chronic musculoskeletal pain in adults, ketoprofen and diclofenac topical products were significantly more effective at reducing pain than the products they were compared with—including both topical and oral NSAIDs—in patients with OA. 25 Topical diclofenac use resulted in pain relief similar to that of oral NSAIDs and had fewer GI side effects. 25 While other topical NSAIDs have been studied, diclofenac and ketoprofen demonstrate the most evidence. Topical NSAIDs may be effective options in patients experiencing mild-tomoderate chronic pain who are at increased risk for renal and GI complications. 22,10,15

Other topical products, including herbal derivatives, are available and may be marketed for chronic pain conditions. However, most of these products have limitedquality evidence. For example, various mint extracts, such as menthol, are often used as topical products for pain relief, but as with most complementary therapies, the evidence is not substantial. 26,27 Products with greater clinical evidence, such as topical NSAIDs, should be recommended over these products when possible.


Tricyclic Antidepressants (TCAs): TCAs are among the antidepressants that are commonly used in patients with neuropathic pain. Some advantages of using TCAs include their extensive history of use for pain management and their low cost. 11 Although they have been employed with success in neuropathic pain conditions, TCAs may not be effective for all pain types. 11 According to a Cochrane review, TCAs were no more effective than placebo for treating chronic low back pain. 18

Numerous potential side effects also complicate treatment due to the TCAs’ anticholinergic profile, including dry mouth, constipation, blurred vision, and sedation. 10 Nortriptyline is associated with fewer of these effects compared with amitriptyline. 10 It is important to instruct patients that they will most likely become tolerant to side effects and that it may take a few weeks to feel pain relief. 11

Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs): SNRIs are another class of antidepressants that has been used in the management of chronic pain. Duloxetine is currently FDA-approved for the management of chronic pain caused by fibromyalgia and has been shown to be effective in at least three other chronic pain conditions, including diabetic peripheral neuropathy, chronic low back pain, and OA of the knee. 11,15

In a pharmacoeconomic study investigating the cost-effectiveness of utilizing duloxetine in chronic pain from OA, duloxetine was more cost-effective than oxycodone and tramadol. 28 Additionally, after considering adverse events, duloxetine was also more cost-effective than naproxen. 28 Venlafaxine extended-release was also shown to be effective in diabetic neuropathy, but is currently not FDA-labeled for the treatment of pain. 11

Based on the effectiveness of SNRIs and the frequency with which patients experience both pain and depression, an adequate trial of an SNRI should be strongly considered for patients in chronic pain. Before initiating an SNRI, be sure that the patient is not taking any medication classified as a monoamine oxidase inhibitor (MAOI), as these are contraindicated with SNRIs. 29-32 Some common adverse effects include nausea, dizziness, fatigue, constipation, and sexual dysfunction. 29,32 It is also important to monitor for changes in mood, especially if there is any suicidal ideation. 30,31


It is thought that, along with antidepressants, anticonvulsants stand as one of the most important adjunctive groups of medications for pain management. 11 Gabapentinoids provide fast pain relief during the titration period and have also been found to improve both sleep and mood. 20 However, time may be required to find the correct dose to balance such pain relief alongside minimal adverse drug events. 20

Gabapentin, Pregabalin: Two medications from the gabapentinoid class, gabapentin and pregabalin, have strong evidence for their use for pain. 11 They are thought to be effective in the treatment of neuropathic pain due to their inhibition of the excitatory neurotransmitters that are prevalent in pain production. 11

Trials utilizing pregabalin consistently demonstrate that it can improve neuropathic pain control while significantly reducing the amount of opioids a patient consumes. 33 Gabapentin is FDA-approved for postherpetic neuralgia (PHN), whereas pregabalin has received FDA approval for PHN and additional pain types including diabetic peripheral neuropathy, fibromyalgia, and neuropathic pain associated with spinal-cord injuries. 15 In 14 trials involving chronic neuropathic pain, 42% of participants had improved pain relief with gabapentin compared with the 19% of those taking placebo. 11

Carbamazepine, Oxcarbazepine: The anticonvulsants of choice for patients suffering from trigeminal neuralgia are carbamazepine and oxcarbazepine. 11 These drugs act on peripheral sodium channels and emit their analgesic effect by blocking synaptic conduction at the trigeminal nucleus. 11 Currently, carbamazepine is FDAapproved for trigeminal neuralgia. Carbamazepine and oxcarbazepine are 3A4 inducers; therefore, it is important to check a patient’s medication list for any potential drug interactions. 11 In addition, similar to the SNRIs, carbamazepine is also contraindicated in patients who are concomitantly taking an MAOI, due to the risk of serotonin syndrome. 11 Another contraindication includes individuals with bone-marrow suppression. 11

As with any medication, it is also important to monitor for any signs of allergy or serious skin conditions. Monitoring should include occasional checks of CBC and changes in mood, such as suicidal ideation. 11 Some common side effects include dizziness, somnolence, and dry mouth.

While other anticonvulsants have been used in pain management, many of them lack evidence or require further research. Two commonly used anticonvulsants include topiramate and lamotrigine. While topiramate has an off-label indication for diabetic neuropathy, the evidence for topiramate is weaker than that for other anticonvulsants and therefore it is not often recommended. 34,35 Based on a Cochrane review, lamotrigine lacked sufficient evidence for use in chronic-pain management. 36


There are various factors to consider when selecting a particular treatment regimen for pain, including comorbid conditions such as cardiovascular risks and GI complications, along with factors including age and concomitant medications. Other comorbidities that may require treatment alteration or consideration based on their pharmacokinetic profile include renal and hepatic failure. 11

Elderly patients are commonly diagnosed with chronic pain conditions, which are often secondary to other conditions. Older adults can be challenging to treat, as their pharmacokinetic and pharmacodynamic characteristics may put them at high risk for adverse events. They may not be able to tolerate NSAIDs or TCAs due to the side-effect profile and other potential drug-related problems. Medications should also be evaluated for their potential to increase the risk of falls. When selecting a therapy for chronic pain, clinicians should follow the adage “start low and go slow” in order to optimize treatment while minimizing the risk for toxicity and adverse drug events. For both non-opioids and opioids, elderly patients should be started on the lowest dose and slowly titrated until analgesic effect is achieved. 10

Overall, when clinicians are choosing a specific treatment for pain, such therapy should be chosen based on effectiveness as demonstrated in clinical trials and the recommendations of evidence-based guidelines. 11 The clinical decision on whether to give opioids, non-opioids, or a combination is challenging and needs to be individualized for each patient. It is important that pain is not ignored, as untreated pain can lead to worsening quality of life and other comorbid conditions. 2


Due to the complexity of treating chronic pain in the setting of an opioid epidemic, it is important for all healthcare team members to become involved, for the benefit of the patient. As medications are commonly used as the primary therapy for pain, the pharmacist’s input and evaluation are crucial. Pharmacists are on the front line for screening for potential opioid abuse and diversion. The pharmacist may evaluate the selection of medication and its dosage in order to reduce potential adverse drug events and improve adherence. 37

Also, as previously mentioned, the pharmacist may play a vital role in evaluating the overall factors for each patient, including their comorbidities, age, and concomitant medications, to determine the appropriateness of the medication selection. Particularly, a pharmacist’s knowledge of a patient’s overall medication profile may prevent duplicate therapy, potential drug-drug interactions, and other drug-related problems. Two systematic reviews evaluating the effectiveness of pharmacist interventions in pain management have proven their importance with regard to both patient satisfaction and statistically significant reduction in pain. 37


In order to treat chronic pain, it is important to identify the location and type of pain. These are important factors that will determine which therapies, both opioid and non-opioid, will be the most efficacious. It is also important to take into account the patient’s past medical history, family history, lifestyle, concomitant medications, and comorbid conditions. While opioids have been the mainstay of therapy in treating chronic pain, it is time to take into consideration the harmful effects that can develop, such as addiction and dependence. Because the U. S. is facing one of the largest opioid epidemics in recent history, it is important to seek out alternative therapies for chronic pain. 1,3

Acetaminophen, NSAIDs, antidepressants, and anticonvulsants are all possible treatment alternatives to opioids when used correctly. Opioids for chronic pain are also a needed intervention for some patients. All medications will have their own unique risks and benefits. Overall, when possible, a trial of non-opioid analgesics should be used for chronic pain. If opioids are needed, non-opioid analgesics should be continued as tolerated in an effort to reduce the amount of opioids required.


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