Pain: Healthcare's Persistent ChallengePage 13 of 21

11. Non-Opioid and Adjuvant Analgesics

A wide variety of non-opioid analgesics are available for the treatment and management of pain. Each has a unique profile and differs in onset, peak action, duration of action, and side effects. A multimodal approach (balanced analgesia), which includes non-opioids, adjuvant medications, and opioids, is recommended.

Non-Opioid Analgesic Agents

The appropriate use of analgesics—the right drug at the right interval—provides good pain relief for the majority of patients. There are dozens, even scores, of drugs that can be used depending on the clinical circumstances. For patients needing “broadly effective analgesia,” non-opioid approaches may offer overall safety and efficacy as compared to opioid analgesics. Rather than immediately moving to opioids, a clinician should consider whether non-opioid approaches may be appropriate (Thomas, 2013).

Nonsteroidal Anti-Inflammatories

A multitude of reports have delineated the risks of using nonsteroidal anti-inflammatory drugs but have not been totally congruent. Meta-analyses of randomized controlled trials sometimes concur regarding gastrointestinal risk and cardiovascular risk but rarely report a balance of these risks for any one drug. Benefits measured in these studies are usually not reported.

Observational data sets, supposedly reflective of “real world” patients, do not always agree with the randomized controlled trial reports. Clinicians need assessments measuring the balance of harms and benefits so that better decisions based on their patients’ unique risk factors can be reached.

Lee S. Simon, 2015
Non-steroidal Anti-inflammatory Drugs and Their Benefits and Harms

Nonsteroidal anti-inflammatory drugs (NSAIDs) are medications with anti-inflammatory, analgesic, and antipyretic properties; they are among the most widely used drugs in the world. They are used to reduce short- and long-term pain, decrease stiffness, and improve function in patients with acute and chronic conditions such as arthritis, headache, dysmenorrhea, and post operative pain. Aspirin, the first NSAID, was developed in 1897.

NSAIDs (non-selective NSAIDs, cyclooxygenase 2 inhibitors [coxibs], and semi-selective NSAIDs), are most commonly prescribed to relieve pain and inflammation. They work by inhibiting cyclooxygenase (COX) enzymes from making prostaglandins, some of which cause pain and inflammation. Because certain prostaglandins protect the stomach lining from the stomach acid that helps to digest food, NSAIDs can cause gastrointestinal (GI) complications. A history of prior gastrointestinal symptoms or bleeding, the presence of other risk factors such as advancing age, higher doses of NSAID, duration of NSAID use, and the frailty of the patient all increase the risk for upper GI damage and consequent bleeding (Simon, 2013).

NSAIDs can be classified according to their mechanism of action:

  • Non-selective NSAIDs like ibuprofen and naproxen inhibit both COX-1 and COX-2 enzymes.
  • Coxibs such as celecoxib (Celebrex) and rofecoxib* are designed to selectively inhibit COX-2 enzymes.

*Rofecoxib (Vioxx) has been withdrawn from the market.

Semi-selective NSAIDs (indomethacin [Indocin], meloxicam [Mobic], and diclofenac [Voltaren]) has a higher affinity for COX-2 but tend to inhibit the COX-1 pathway also (Ghosh et al., 2015). COX selectivity is one of the determining factors to consider when giving NSAIDs to a patient.

A meta-analysis of more than 700 studies involving the use of certain NSAIDs for pain was conducted by the The Coxib and Traditional NSAID Trialists’ (CNT) Collaboration. Researchers looked at the risk of major vascular events, major cardiac events, and upper GI complications from high-dose, long-term use of certain NSAIDs. Concerns about the possible heart risks of NSAIDs, many of which have been on the market for several decades, arose after randomized trials showed that coxibs increased the risk of heart attacks (MRC, 2013).

Diclofenac (Voltaren) is the agent currently in use that is most associated with an increased risk of cardiovascular events: a 40% to 60% higher relative risk of serious cardiovascular events, compared to non-use of NSAIDs, has been reported. This is a rate equivalent to or possibly higher than that of rofecoxib (Vioxx), now withdrawn from the market (McGettigan & Henry, 2013).

In contrast, another traditional NSAID, naproxen, has been found to be relatively benign, with a cardiovascular risk that was observed to be neutral or much lower than that of diclofenac (McGettigan & Henry, 2013). The CNT Collaboration report indicated that naproxen might be safer for patients with cardiovascular risk but that it is one of the worst NSAIDs in terms of risk for a major GI complication (Simon, 2015).

Regardless of their mechanism of action, prolonged exposure to any class of NSAIDs has been shown to have potential adverse cardiovascular effects in patients with or without pre-existing cardiovascular conditions, depending on the duration and dosage of these drugs. Patients with pre-existing cardiovascular conditions such as coronary artery disease, hypertension, and history of stroke are at the greatest risk of cardiovascular events after taking NSAIDs. Patients who have recently had cardiovascular bypass surgery are advised not to take NSAIDs due to a high risk of heart attacks (Ghosh et al., 2015).

NSAID guidelines have been established to increase physician awareness of the complications associated with NSAID use; however, some physicians either do not recognize or do not adhere to such guidelines (Taylor et al., 2012). A recent survey of physicians identified six major barriers that affected their use of established NSAID guidelines:

  1. Lack of familiarity with the guidelines
  2. Perceived limited validity of the guidelines
  3. Limited applicability of the guidelines to specific patient populations
  4. Clinical inertia
  5. Anecdotal experiences
  6. Clinical heuristics (experience-based problem solving, learning by trial and error rather that following a pre-established formula) (Taylor et al., 2012)


Acetaminophen, the active ingredient in Tylenol, is also known as paracetamol and N-acetyl-p-aminophenol (APAP), and has been marketed in the United States as an OTC antipyretic and analgesic agent since 1953. It is widely available in a variety of strengths and formulations for children and adults as a single-ingredient product.

Although acetaminophen has been in clinical use for decades, its mechanism of action is not fully understood. It is thought to inhibit cyclooxygenases both centrally and peripherally. Researchers have suggested that the inhibition of cyclooxygenase in the brain is responsible for the antipyretic effect of acetaminophen, suggesting a central mechanism of action. Some have suggested classifying acetaminophen as an atypical NSAID (Chavez et al., 2015).

At the same time, research has been conducted showing that acetaminophen is a prodrug,* and indicating that the analgesic effect of acetaminophen arises from the indirect activation of cannabinoid CB1 receptors. Acetaminophen also has an effect on the descending serotonergic pathway, and may interact with opioidergic** systems or nitric oxide pathways—and also may act as a selective COX-2 inhibitor in humans (Chavez et al., 2015).

*Prodrug. A prodrug is a medication or compound that, after administration, is metabolized into a pharmacologically active drug (Wikipedia, 2016).

**Opioidergic. An opioidergic agent is a chemical that functions to directly modulate the opioid neuropeptide systems (i.e., endorphin, enkephalin, dynorphin, nociceptin) in the body or brain.

Acetaminophen is used in combination with many prescription opioid drugs (Vicodin, Percocet) to give more pain relief while minimizing the dose of the addictive narcotic component. It is generally considered safe at recommended doses, but if more is taken—even just a little more—it can cause serious and even fatal liver damage. In fact, acetaminophen poisoning is a leading cause of liver failure in the United States (Hodgman & Garrard, 2012).

In the United States, acetaminophen is available as 325 mg and 500 mg preparations and as a 650 mg extended-release medication intended for arthritis treatment. It is available in drops, capsules, and pills, as well as various children’s dissolvable, chewable, and liquid formulations. To reduce the risk of accidental overdose, in 2014 the FDA announced that medications containing a combination of acetaminophen and an opioid can no longer contain more than 325 mg of acetaminophen per tablet or capsule.

Video (1:53) Prescription Acetaminophen/Opioid Combinations: Making Pain Medicines Safer (2014)

Although acetaminophen is effective as an antipyretic and analgesic, its anti-inflammatory properties are much weaker than those of aspirin and other NSAIDs. It is therefore less effective for chronic inflammatory pain conditions such as rheumatoid arthritis. Acetaminophen is, however, a good choice for osteoarthritis, especially in those patients where aspirin is contraindicated. Acetaminophen lacks the antithrombotic, blood-thinning properties of aspirin and other NSAIDS and therefore does not inhibit coagulation, an important consideration for pain therapy following minor surgical or dental procedures.

From both a GI and cardiovascular perspective, acetaminophen may not be as safe as previously believed—especially at doses higher than 3 g daily. Indeed, a nested case-control study found that use of acetaminophen (any dose) is associated with a small but significant risk of upper GI complications. In addition, although women from the Nurses’ Health Study, who reported occasional use of acetaminophen, did not experience a significant increase in the risk of cardiovascular events, those who reported a frequent use (6–14 tablets/week) had a small increased risk (Scarpignato et al., 2015).

Regular acetaminophen has also been associated with an increased risk of hypertension both in women and men. At doses of 3 g daily, acetaminophen induces a significant increase in ambulatory blood pressure in patients with coronary artery disease. These findings are not surprising in the light of the recent discovery that acetaminophen is indeed a selective cyclooxygenase (COX)-2 inhibitor in humans (Scarpignato et al., 2015).

Acetaminophen has been associated with a risk of rare but serious skin reactions. These skin reactions, known as Stevens-Johnson syndrome, toxic epidermal necrolysis, and acute generalized exanthematous pustulosis, can be fatal. These reactions can occur with first-time use of acetaminophen or at any time while it is being taken. Other drugs used to treat fever, pain, and body aches (eg, NSAIDS, such as ibuprofen and naproxen) also carry the risk of causing serious skin reactions, which is already described in the warnings section of their drug labels (FDA, 2013b).

Because the risks of acetaminophen-related liver damage are so serious and because the public is often unaware of these risks, the National Council for Prescription Drug Programs, the FDA’s Safe Use Initiative, and other stakeholders met in 2011 to form the Acetaminophen Best Practices Task Group. The Task Group recommendations, updated in 2013, are intended to make it easier for consumers to identify whether a prescription pain reliever contains acetaminophen, to compare active ingredients on labels, and to take action to avoid taking two medicines with acetaminophen. The Task Group recommended coordinating prescription container labeling with the labeling that already exists for OTC medicines, providing consistency in labeling across all acetaminophen-containing medicines (FDA, 2013a).

Use of NSAIDs and Acetaminophen in Older Adults

Nonsteroidal anti-inflammatory drugs have been a mainstay for chronic pain management for many years but should be used with caution in older adults (Age and Ageing, 2013). Adverse reactions associated with NSAIDs including GI, cardiovascular, renal, and hematologic side effects, have been known for a long time. Introduction of new drugs into the marketplace and the continual stream of new research data have recently called into question the use and prescribing guidelines of NSAIDs in elders, especially “complex” older patients (Taylor et al., 2012).

Prescribing NSAIDs to older adults requires knowledge of individual patient risk factors, benefits and risks of the NSAID, and patient education. Monitoring for effectiveness and side effects is essential. A recent report demonstrated that more than 50% of patients were not properly informed by a physician or pharmacist on the side effects associated with prescribed or OTC NSAIDs (Taylor et al., 2012).

For older adults, acetaminophen is the first-line treatment for both acute and persistent pain, particular musculoskeletal pain. Acetaminophen has a good safety and efficacy profile as long as the maximum daily dose of 4g/24h is not exceeded (Age and Ageing, 2013).

Nitrous Oxide (N2O)

Based upon the recent literature, N2O may be poised for something of a comeback in the acute care setting. The agent is well known, self-administered, safe, and at least moderately effective. It avoids the need for IV access and has a very low risk of side effects. It is excreted unchanged by the lungs so there are no issues with renal or hepatic disease. When the training, technical, and related physical barriers (eg, external venting) to N2O use in the ED can be overcome, it makes sense for an ED to have this inhaled agent available for analgesia and also as an adjunct for procedural sedation (Thomas, 2013).

As an inhaled, rapid-onset short-acting analgesic in doses used in acute care (generally 50:50 with oxygen but sometimes at higher concentrations for cities at higher altitudes), N2O has been in effective use in the prehospital and ED settings for many decades. Its onset and offset times of roughly 3 to 5 minutes contribute to N2O’s potential utility in the acute care environment. The gas has been reported useful for analgesia for acute conditions ranging from procedures to acute intensely painful conditions in which traditional analgesia is difficult (Thomas, 2013).

Medical Cannabis

Cannabis has an unrivaled history of continuous cultivation, having started in Neolithic China more than 6000 years ago. A thorough scientific evaluation of the medical use of cannabis goes back to the work of Sir William B. O’Shaughnessy in 1838–1840. Since then cannabis has been intensively investigated. In the early 1960s cannabidiol (CBD) and the most psychoactive cannabinoid delta-9-tetrahydrocannabinol (THC) were identified. By 2009 more than 525 constituents have been identified, among them about a hundred different cannabinoids (Lanz et al., 2016).

In addition to THC, other cannabinoids (and non-cannabinoids, such as terpenoids*) likely contribute to and modulate the overall pharmacologic effects of cannabis. Numerous recent studies have proven the anti-inflammatory and neuroprotective properties of THC and CBD. Cannabidiol is known to reduce the psychotropic effects of THC; in addition, THC and CBD act synergistically (Lanz et al., 2016).

*Terpenoid: a terpene is a hydrocarbon found in the essential oils of many plants, especially conifers and citrus trees. Terpenes are also found in cannabis plants; terpenoids are formed when cannabis is dried and cured. Terpenes are non-cannabinoids and are responsible for the distinctive smell of cannabis.

There is growing evidence that the cannabinoid receptor system plays a central role in the regulation of many key functions to maintain homeostasis. Tetrahydrocannabinol, which is a partial agonist to CB1 receptors and to a smaller extent to CB2 receptors, is available in many countries for several indications. It is administered orally to treat pain, nausea, spasticity, and loss of appetite. It has proven to be effective in patients suffering from cancer, multiple sclerosis, amyotrophic lateral sclerosis, chronic pain, and other diseases (Lanz et al., 2016).

All animals except insects have an endogenous (made within the body) cannabinoid system, or endocannabinoid system (ECS). It has been found that humans make cannabinoids, similar in structure to those of the cannabis plant; further, humans have receptors for these molecules. This newly discovered molecular signaling system is essential for life and helps keep us in balance as we deal with daily stressors (Mathre, 2016).

Cannabinoid receptors in the human brain were first identified in 1988 by American researcher Allyn Howlett and her graduate student William Devane. They named these receptors cannabinoid 1 (CB1) receptors. In 1992 researchers in Israel discovered an endogenous cannabinoid neurotransmitter, which they called anandamide. By 1993 another group of scientists found cannabinoid receptors in the immune system (CB2). To date five endocannabinoids have been discovered.

The CB1 receptors are found mainly on neurons in the brain, spinal cord, and peripheral nervous system, but are also present in other organs and tissues. The low number of CB1 receptors in the brain stem may help explain the absence of cannabis overdoses due to the depression of respirations. CB2 receptors are primarily found in immune cells, among them leukocytes, the spleen, and tonsils.

The effectiveness of cannabis in decreasing pain is thought to be related to the role of the CB2 cannabinoid receptor, which suppresses microglial cell activation and decreases neuro-inflammation. In addition, cannabinoid receptors may couple to other effectors that are critical for the transmission of pain signals (Gadotti et al., 2013).

Pharmaceutical researchers are exploring the potential therapeutic properties of the cannabinoid system while attempting to minimize problematic side effects. A significant problem surrounding the medical use of cannabis-related compounds is a concern regarding their CB1-mediated psychoactive effects and abuse potential. The interest in developing compounds whose mechanism of action involves CB2 receptors without CB1 involvement remains a goal in medical therapeutics. For this reason, selective CB2 receptor ligands appear as potentially viable compounds for pain management (Gadotti et al., 2013).

Several peer-reviewed studies conducted at University of California, San Diego have shown the value of cannabis for some pain-related conditions. One study looked at the effect of cannabis on HIV-related peripheral neuropathy and found that pain relief was greater with cannabis than placebo. Additionally, mood and daily functioning improved among the group using cannabis for pain relief. In another study, researchers looked at the effect of smoked cannabis on 30 participants with spasticity due to multiple sclerosis. Results indicated that smoked cannabis was superior to placebo in symptom and pain reduction in participants with treatment-resistant spasticity (Corey-Bloom et al., 2012).

The Food and Drug Administration recently approved an investigational new drug study of purified CBD. The new drug, called Epidiolex, is provided by a British company called GW Pharmaceuticals. The drug will be used for the treatment of pediatric epilepsy in small studies at the University of California San Francisco and the NYU School of Medicine.

Adjuvant Medications

Adjuvant analgesics (or co-analgesics) are drugs with a primary indication other than pain that have analgesic properties. Although not primarily identified as an analgesic in nature, they have been found in clinical practice to have either an independent analgesic effect or additive analgesic properties when used with opioids (Khan et al., 2011). This group includes drugs such as antidepressants, anticonvulsants, corticosteroids, neuroleptics, and other drugs with narrower adjuvant functions. Adjuvant drugs can be used to enhance the effects of pain medications, treat concurrent symptoms, and provide analgesia for other types of pain. Adjuvant analgesics are particularly useful when evidence of decreased opioid responsiveness is present (Prommer, 2015).

Adjuvants commonly used to enhance the effects of pain medications include:

  • Antidepressants
  • Anticonvulsants
  • Local anesthetics
  • Corticosteroids
  • Bisphosphonates