OR: Pain, Healthcare's Persistent Challenge, 6 unitsPage 14 of 22

12. 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

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*Rofecoxib (Vioxx) has been withdrawn from the market.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

Acetaminophen has been in clinical use for decades, yet 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 shown 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 (ie, endorphin, enkephalin, dynorphin, nociceptin) in the body or brain.

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.

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).

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


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, 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 (Scarpignato et al., 2015).

Because the risks of acetaminophen-related liver damage are so serious and because the public is often unaware of these risks, the Acetaminophen Best Practices Task Group has published recommendations 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 also 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). 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 older adults, especially “complex” older patients (Taylor et al., 2012).

Adverse reactions associated with NSAIDs including GI, cardiovascular, renal, and hematologic side effects, have been known for a long time (Age and Ageing, 2013). 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).

Medical Cannabis

In the early 1960s cannabidiol (CBD) and the psychoactive cannabinoid delta-9-tetrahydrocannabinol (THC) were identified in cannabis (Lanz et al., 2016). Cannabinoid 1 (CB1) receptors in the human brain were first identified in 1988. 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. By 2009 more than 525 constituents have been identified, among them about a hundred different cannabinoids.

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. CBD is known to reduce the psychoactive 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.

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. There are only a small number of CB1 receptors in the brainstem, which 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).

THC, which is a partial agonist* to CB1 receptors and to a smaller extent to CB2 receptors, is available in many countries and 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).

*Partial agonist: an agonist activates certain receptors in the brain. A partial agonist binds to and activates receptors in the brain but not as strongly as a full agonist. A partial agonist can also compete with a full agonist for a receptor site, lessening the effectiveness of the full agonist.

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).

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
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