Shopping Cart

INTRODUCTION

Providing safe, compassionate patient care requires clinicians to provide effective pain management while minimizing adverse effects and avoiding toxicities. The risks of opioids have deservedly received much attention. However, other drug classes used to manage pain also have risks, and these must be accounted for and managed appropriately.

This program reviews the approach to pain management and the pharmacology of analgesics, an understanding of which underlies safe and effective pain management.

The burden of pain in the United States is significant, with more than 120 million adults reporting pain in the prior 3 months and 25 million reporting chronic daily pain.¹ Not only does pain affect patients’ quality of life, pain is an indicator of increased mortality risk, greater resource utilization, and patient disability.^1,2 The need to improve pain management has led the International Association for the Study of Pain to call for improvement in training of healthcare providers arguing, “…the system of pain care delivery in the United States has not kept pace with societal needs or the public’s expectations for accessible, quality pain care.”³

The need to improve pain management has also highlighted the challenges of safely using pharmacologic treatments, namely opioids. The opioid crisis has reached epidemic levels in the United States, with 20% of all deaths among adults aged 24–35 years attributable to opioids. The years of lost life attributable to opioids now exceeds the number associated with cancer by 10-fold. Opioid-related deaths have increased dramatically in the United States, rising 345%, from 33.3 deaths per million population in 2001 to 130.7 in 2016. Furthermore, opioid-related deaths have increased across all age groups; while the largest absolute increase in deaths has occurred among adults aged 24–35 years, the largest relative increase in deaths has occurred among 55–64 year olds.⁴ Although the opioid epidemic was first considered to be one of prescription opioid misuse, use of illicit opioids such as heroin has increased dramatically and often begins with the misuse of prescription opioids.⁵

CHARACTERIZING PAIN

Providing safe and effective pain management starts with an understanding of the cause of a patient’s pain, its time course, and its likely pathology. Differentiating between acute and chronic pain, as well as between nociceptive and neuropathic pain is essential, because it enables clinicians to choose the most effective treatment plan for the patient.

Acute pain is short-term pain associated with injury and resolving with healing. It generally lasts 3 to 7 days. Chronic pain is defined as pain persisting past the expected duration of healing from an initial injury. It is generally present for 3 to 6 months.⁶

Most acute pain is nociceptive; in other words, it is a healthy response to painful stimulus that resolves with healing. Acute pain serves a protective function by providing a warning that tissue damage is occurring or may occur. It is typically described as sharp or achy, and it is localized.

In contrast, neuropathic pain is indicative of injury to the pain-processing system itself; for example, painful diabetic neuropathy is caused by damage to nerves. Unlike nociceptive pain, neuropathic pain is described as tingling, burning, or electric shock-like, and may be diffuse or radiating. Accurately identifying pain as acute or chronic and nociceptive or neuropathic is essential to selecting appropriate treatment modalities.

APPROACH TO ACUTE PAIN MANAGEMENT

The cornerstone of acute pain management is facilitating healing of the original injury. RICE therapy — rest, ice, compression, and elevation — is an important nonpharmacologic strategy to relieve pain and facilitate healing of acute musculoskeletal injuries.

First-line pharmacologic therapy for acute pain relies on use of nonopioids such as acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs).⁷ Selection of a first-line pharmacologic therapy depends on a patient’s co-morbidities; NSAIDs may not be appropriate for patients with renal dysfunction or asthma, or in those at increased risk of gastrointestinal bleeding or cardiovascular events.^7,8 Topical NSAIDs are an important alternative to systemic NSAIDs and may provide similar efficacy for localized pain without the risks of serious adverse effects associated with systemic NSAIDs.^8-10

A recently published overview of Cochrane reviews examined the use of over-the-counter analgesics for acute postoperative pain. It concluded that combination treatment with ibuprofen and acetaminophen provided the greatest efficacy, with nearly 70% of patients achieving at least 50% pain relief over 4 to 6 hours (number needed to treat [NNT] <2). Ibuprofen alone at a dose of 200 mg to 400 mg, ibuprofen 200 mg in combination with caffeine 100 mg, and diclofenac potassium 50 mg were also highly efficacious, with more than 50% of patients achieving at least 50% pain relief and a NNT of about 2. Acetaminophen alone and aspirin were less effective, with 11% to 43% of patients achieving at least 50% pain relief and a NNT of more than 3. All agents were found to be safe, with adverse event rates similar to placebo.¹¹

Opioids may be appropriate for management of severe acute pain.^{6, 7} If necessary, opioids should be prescribed at the lowest effective dose and for the shortest possible duration. The Centers for Disease Control and Prevention (CDC) guideline for the use of opioids in chronic pain recommends no more than a 7-day duration of opioids for acute pain, and recommends 3 days or less as sufficient for most acute pain management.⁶ Extended-release and long-acting opioid formulations are not appropriate for acute pain management.

APPROACH TO CHRONIC PAIN MANAGEMENT

Chronic pain management should focus on improving patient function and quality of life, with the understanding that complete pain relief is unlikely to be achieved. Clinicians must set realistic expectations with patients, recognizing that a 30% to 50% reduction in pain intensity and improvement in function are appropriate targets of pain management. Chronic pain care involves a multimodal approach, including pharmacologic and nonpharmacologic treatments combined with self-care to improve patients’ quality of life.⁸

The CDC guideline for the use of opioids in chronic pain emphasizes that opioids should not be used first line for chronic pain; nonpharmacologic approaches and nonopioids are preferred instead.⁶ A trial of acetaminophen is considered first-line pharmacologic therapy for chronic pain. For chronic pain that is neuropathic in nature, tricyclic antidepressants (TCAs), gabapentin, or pregabalin may be utilized, with topical lidocaine or capsaicin potentially useful for well-localized pain.⁸

A 2015 systematic review and meta-analysis by Finnerup and colleagues evaluated more than 200 studies of pharmacologic treatments for neuropathic pain and found the NNT to achieve 50% pain intensity reduction was lowest for tricyclic antidepressants (TCAs; NNT, 3.6). Serotonin-norepinephrine reuptake inhibitors (SNRIs) were modestly effective with a NNT of 6.4, while gabapentin and pregabalin were found to be have NNTs of 6.3 and 7.7, respectively. Capsaicin patches were even less effective and topical lidocaine patches could not be evaluated due to lower quality evidence.¹²

While TCAs were shown to be more effective than other pharmacologic options for neuropathic pain, they are also less well tolerated. Overall, the authors provided a strong recommendation that TCAs, SNRIs, pregabalin, gabapentin, and gabapentin enacarbil as first-line agents in neuropathic pain. Lidocaine patches, tramadol, and capsaicin patches were given a weak recommendation for consideration as second-line agents, while opioids and botulinum toxin A (BTX-A) were given a weak recommendation for use as third-line agents.¹²

NSAIDs can be considered for chronic nociceptive pain, but adverse effects necessitate careful consideration of patient age and comorbidities.⁸ Topical NSAIDs may be preferred, particularly in adults age 65 years or older, those with comorbidities, or those requiring long-term therapy because of their low systemic absorption and reduced risk of adverse effects.^8-10

Opioids (see Table 2) may be appropriate for chronic pain management in limited circumstances when the potential benefits for both pain and patient function outweigh their risks. Before initiating treatment, providers should discuss the potential risks and benefits of opioid therapy, as well as provider and patient responsibilities.⁶

The recently published SPACE randomized clinical trial suggests the benefits of opioids in chronic pain are minimal. Investigators compared the effects of opioids and nonopioids on pain-related function, intensity, and adverse effects in 240 patients with chronic pain caused by back problems or knee or hip osteoarthritis over 1 year. Pain-related function and intensity were assessed using the Brief Pain Inventory (BPI) interference and severity scales, respectively. Medication-associated adverse effects were assessed by patient-reported symptoms.¹³

Notably, this study was conducted at Veterans Affairs clinics, so patients included in this trial may not be representative of the general population and likely over-represent men. Patients with current opioid dependence or those already using chronic opioids for pain management were excluded. Patients were randomized to receive opioid or nonopioid medications. Patients randomized to receive opioid therapy were first started on immediate-release oral opioids, with therapy progressing to long-acting opioids and/or long-acting opioids in combination with short-acting opioids for breakthrough pain if needed. Patients in the nonopioid treatment group first received acetaminophen or NSAIDs, with therapy progressing to include adjuvant agents if needed.¹³

There was no significant difference in pain-related functioning between patients receiving opioids and those receiving nonopioids. Pain intensity was statistically significantly improved for patients receiving nonopioids compared with those receiving opioids, although the relative improvement in pain intensity was small and may not be clinically important.¹³

Nonpharmacologic treatments demonstrated to be beneficial for patients with chronic pain include cognitive-behavioral therapy, physiotherapy, peripheral nerve stimulation, and acceptance and commitment therapy. Acupuncture also has demonstrated efficacy for osteoarthritis and low back pain. There is little evidence supporting the use of osteopathy, chiropractic care, homeopathy, or herbal treatments. Self-care for chronic pain includes “activities which ‘enhance function, improve mood and decrease pain’ by targeting and challenging the ‘emotional, cognitive, and behavioral responses to pain,’” including techniques such as mindfulness.⁸ Self-care resources for patients suffering from chronic pain can be found at paintoolkit.org.¹⁴

PHARMACOLOGY

Acetaminophen

Acetaminophen is considered a first-line analgesic for most patients because of its overall safety profile and tolerability. It also has antipyretic activity. Acetaminophen has weak anti-inflammatory properties and provides analgesia by inhibiting prostaglandin synthesis through inhibition of the cyclooxygenase (COX) pathway. It has also been proposed to provide analgesia through the endocannabinoid system and the descending serotoninergic inhibitory pathway.¹⁵

Acetaminophen is safe for use in patients with renal dysfunction, although the dosing frequency should be reduced in those with severe renal impairment. it has few drug–drug interactions.⁷ It is also considered safe in pregnancy. Unlike NSAIDs, it does not increase blood pressure.

The most serious adverse effect associated with acetaminophen is hepatotoxicity. To avoid hepatotoxicity, the maximum dose of acetaminophen from all sources, including over-the-counter medications, cough and cold preparations, and pain medications is 4 g/d. Due to the potential for additive hepatotoxicity, acetaminophen should not be used in combination with alcohol. If patients are consuming alcohol while taking acetaminophen-containing medications, the maximum daily dose of acetaminophen should be reduced to 3 g/d. A maximum acetaminophen dose of 2–3 g/d should also be used in patients with hepatic impairment and adults age 65 years or older.^16,17

In the United States, half of acute liver failure cases are caused by drugs, and 80% of those cases are from acetaminophen overdose. Acetaminophen hepatotoxicity is caused by a minor metabolite, N-acetyl-p-benzoquinoneimine (NAPQI), which is electrophilic and depletes hepatic glutathione. Importantly, the NAPQI metabolite, while minor, is formed by metabolism of acetaminophen by the cytochrome P450 (CYP) enzyme system, which shows considerable genetic variation. CYP1A2, CYP2E1, and CYP3A4 are the main CYP isoforms responsible for the formation of NAPQI, with CYP2E1 being the chief isoform when acetaminophen is present in large concenctrations. Genetic variation in the expression of various CYP isoforms underlies the interindividual variability in response to exposure to potentially toxic doses of acetaminophen. N-acetylcysteine (NAC) is an antidote to acetaminophen overdose that prevents toxicity by repleting glutathione concentrations. Glutathione then binds NAPQI, creating a nontoxic conjugate.¹⁷

Nonsteroidal Anti-inflammatory Drugs

NSAIDs are also considered first-line analgesics; they also provide anti-inflammatory as well as antipyretic activity. Analgesia is achieved through inhibition of prostaglandin synthesis by reversible inhibition of cyclooxygenase (COX).^7,15 Most NSAIDs inhibit both the COX-1 and COX-2 isoforms; inhibition of COX-2 mediates analgesia but can also affect renal function and healing.^7,15,18 Inhibition of COX-1 is associated with gastrointestinal (GI) adverse effects, increased bleeding risk, and alterations in renal blood flow.^7,15,19

While COX-2–selective agents may be preferred for their lower risk of gastrointestinal bleeding, they cost more than nonselective agents. Among nonselective NSAIDs, ibuprofen has been associated with a lower risk of GI adverse effects.²⁰ Indomethacin and ketorolac have been associated with higher rates of GI toxicity, particularly among older patients.⁷

Nonselective NSAIDs may be combined with a proton pump inhibitor (PPI) or misoprostol to provide protection against gastrointestinal bleeding.⁷ A 2016 systematic review and meta-analysis conducted by Yuan and colleagues compared the risk of gastrointestinal adverse events among patients taking nonselective NSAIDs, COX-2–selective NSAIDs, and nonselective or COX-2–selective NSAIDs in combination with a gastroprotective agent such as a PPI, histamine-2 receptor antagonist (H2RA), or misoprostol. The authors analyzed 82 trials of more than 125,000 patients and determined use of COX-2–selective NSAIDs in combination with PPIs was associated with the lowest risk of gastrointestinal adverse effects. Use of COX-2–selective NSAIDs alone and nonselective NSAIDs in combination with PPIs were associated with the second and third lowest gastrointestinal risk, respectively.²¹

Unfortunately, use of PPIs for GI protection from NSAIDs is not without risk; co-prescribing of PPIs with NSAIDs has been associated with a reduction in upper GI adverse effects but an increased frequency of lower GI adverse effects. Upper GI adverse effects result from increased acidity, and thus their risk can be decreased by use of acid-suppressive agents such as PPIs, H2RAs, and misoprostol.²⁰

In contrast, lower GI adverse effects are caused by the acidity of the NSAID molecule itself , and thus cannot be prevented by use of acid-suppressive therapies.²⁰ NSAIDs that are less acidic and thus pose a lower risk of lower GI adverse effects include celecoxib and ibuprofen.²⁰ Risk factors for NSAID-associated GI adverse effects include: age greater than 60 years, history of dyspepsia or uncomplicated peptic ulcer, higher NSAID dose, concurrent use of corticosteroids or anticoagulants, Helicobacter pylori infection, cigarette or alcohol use, and cardiovascular disease.^7,20

The most recent clinical guidelines suggest patients at high risk of NSAID-induced GI complications using nonselective NSAIDs should also take PPIs for upper GI protection.^19,22 Alternatively, patients at high risk could use COX-2–selective agents.²³ Because PPIs present their own risks, and do not protect from lower GI adverse effects, they should not be co-prescribed for all patients taking NSAIDs.²⁰

Increased risk of cardiovascular events is another serious risk associated with NSAID use. Cardiovascular toxicity results from multiple actions of NSAIDs, including changes in endothelial function, oxidative stress, fluid retention, and hypertension.^18,24 A 2011 meta-analysis evaluated 31 studies of more than 116,000 patients taking NSAIDs or placebo to determine the risk of myocardial infarction (primary outcome) and stroke, cardiovascular death, and all-cause mortality (secondary outcomes).²⁵

While cardiovascular harm is a risk with any NSAID, naproxen was associated with the least cardiovascular harm of all NSAIDs included in this meta-analysis.²⁵ The relative cardiovascular safety of NSAIDs is equivocal, with another study evaluating cardiovascular risk finding celecoxib to be noninferior to naproxen and ibuprofen.²⁶ A recent evaluation of diclofenac in comparison to other NSAIDs and acetaminophen found an increased risk of cardiovascular adverse events associated with diclofenac use.²⁷

COX-1 and COX-2 are also constitutively expressed in the kidney and are essential to maintaining renal function.²⁴ Prostaglandins, whose production is inhibited by NSAIDs, regulate both renal vascular tone and sodium balance.^7,24 Inhibition of COX enzymes can lead to decreased renal blood flow and sodium retention.²⁴ NSAIDs can also cause hyperkalemia and hyponatremia due to fluid retention through decreased production of renin and aldosterone. Although NSAIDs can cause clinically significant renal dysfunction, this risk is relatively low and occurs in fewer than 1% of patients. Those patients at risk of NSAID-associated renal toxicity include those with congestive heart failure, volume depletion, hepatic impairment, hyponatremia, hypertension, advanced age, or concomitant drug therapy with diuretics or ACE inhibitors. Patients taking multiple NSAIDs or those using NSAIDs on a long-term basis are also at higher risk of renal toxicity.²⁴

While all NSAIDs carry the same boxed warning regarding cardiovascular and renal toxicity, topical NSAIDs are thought to pose a significantly lower risk of these adverse effects because they produce only minimal systemic concentrations.⁹ In fact, the incidence of adverse effects for topical NSAIDs is similar to placebo, with the most common adverse effect being local application site reactions.¹⁰

In the United States, available topical NSAID formulations approved for treatment of pain include diclofenac sodium 1% gel (Voltaren Gel), diclofenac sodium topical solution 1.5% 2/2 in 45.5% dimethyl sulfoxide (Pennsaid), and diclofenac epolamine 1.3% (Flector Patch). Topical NSAIDs are safe and effective for management of localized pain because of their ability to achieve high drug concentrations at the site of pain while producing low systemic concentrations. Localized activity can also avoid drug–drug interactions associated with systemic NSAID formulations.⁹

Tricyclic Antidepressants

TCAs interfere with the conduction and transmission of pain impulses and modulate pain perception by inhibiting reuptake of serotonin and/or norepinephrine and by blocking sodium channels.²⁸ While TCAs are effective analgesics for neuropathic pain, their use is mainly limited by their anticholinergic adverse effects, which may be particularly problematic for older patients (see Table 1).^12,28

TCAs should also be used cautiously in patients with cardiac disease, glaucoma, and those at risk of seizure, including patients concurrently taking tramadol.²⁸ Dose reduction is not required for patients with renal or hepatic impairment; however, TCAs should be used cautiously in patients with end-organ impairment as they are hepatically metabolized and renally eliminated.^12,16,28

Although they are considered first-line agents for neuropathic pain, TCAs are not approved by the Food and Drug Administration (FDA) for pain management, and their use in this indication is off label.^12,16 FDA approval of TCAs for pain management indications is unlikely, given their currently widespread and accepted use in pain management, and the generic availability of these agents making investment in the required clinical trials unlikely.

Serotonin-Norepinephrine Reuptake Inhibitors

SNRIs such as duloxetine, venlafaxine, and milnacipran produce analgesia by inhibiting reuptake of serotonin and norepinephrine, which decreases conduction and transmission of pain impulses. The most common adverse effect is nausea. SNRIs can increase blood pressure, and milnacipran can increase heart rate, necessitating caution when used in patients with cardiac disease.^12,16,28

SNRIs should be used with caution in patients with hepatic or renal dysfunction. Duloxetine and milnacipran should not be used in patients with a creatinine clearance of less than 30 mL/min or in those with end-stage renal disease. Doses of venlafaxine should also be reduced in the presence of renal impairment.¹⁶

SNRIs can increase the risk of bleeding, particularly when used in combination with NSAIDs. Other serious adverse effects include serotonin syndrome (the risk of which is increased when used concomitantly with other serotonergic agents, such as TCAs) and syndrome of inappropriate antidiuretic hormone secretion and hyponatremia.¹⁶

Upon discontinuation, SNRIs should be tapered over 2 to 4 weeks, as abrupt discontinuation could produce withdrawal or worsening of symptoms. Among the SNRIs, duloxetine is approved by FDA for use in fibromyalgia, painful diabetic neuropathy, and chronic musculoskeletal pain, while milnacipran is approved by FDA for use in fibromyalgia.¹⁶ Pain management with venlafaxine, or with duloxetine or milnacipran outside of their FDA-approved indications, is considered off-label usage.

Gabapentinoids

Gabapentin and pregabalin produce analgesia by binding to the alpha-2-delta-1 subunits of voltage-gated calcium channels and decreasing release of excitatory neurotransmitters. This reduces transmission of pain sensation to the brain, resulting in analgesia.¹⁶

The most common adverse effects associated with gabapentin and pregabalin are dizziness and drowsiness. In order to avoid excessive drowsiness, the drugs should be initiated at a low doses and titrated slowly to effect. Peripheral edema occurs in up to 8% of patients treated with gabapentin and up to 16% of patients treated with pregabalin; these agents should be used with caution in patients with New York Heart Association III or IV heart failure. Gabapentin and pregabalin also require dose adjustment in patients with renal dysfunction. Gabapentin and pregabalin are not metabolized, leading to few pharmacokinetic drug-drug interactions and making them potentially attractive agents for patients taking multiple medications.^12,16,28

Upon discontinuation, gabapentin and pregabalin should be tapered gradually rather than stopped abruptly. Gabapentin is approved by FDA only for management of pain from postherpetic neuralgia, while pregabalin is approved by FDA for pain management in patients with diabetic peripheral neuropathy, fibromyalgia, neuropathic pain secondary to spinal cord injury, and postherpetic neuralgia.¹⁶ While the FDA-approved indications for pain management are somewhat limited for gabapentin and pregabalin, both are considered first-line agents for the management of neuropathic pain.¹²

Topical Lidocaine

Topical lidocaine provides local anesthesia by blocking sodium channels, resulting in decreased sodium entrance to neurons, which inhibits neuronal depolarization and prevents conduction of pain impulses.^12,16 Because of its local action, systemic adverse effects are avoided; the most common adverse effects are erythema or rash at the application site.¹²

Because topical lidocaine patches are applied directly to the site of pain, they are not appropriate for patients with diffuse or poorly localized pain. Although topical lidocaine can be used off-label for patients with well-localized pain, its FDA-approved use for pain management is in postherpetic neuralgia.¹⁶

Capsaicin

Capsaicin is an activating ligand for the transient receptor potential vanilloid 1 receptor (TRPV1). Repeated exposure results in sensory axon desensitization and inhibition of pain transmission through depletion of substance P, which is required for transduction of pain impulses from the periphery to the central nervous system. While available as both an over-the-counter product for musculoskeletal pain, and a topical patch for neuropathic pain, capsaicin is not widely used because of limited evidence supporting its efficacy and poor tolerability. Nevertheless, capsaicin is approved by FDA for use in arthritic pain, musculoskeletal pain, and neuropathic pain due to postherpetic neuralgia or diabetic neuropathy.¹⁶

Among patients using topical capsaicin patches, 63% report erythema and 42% report pain at the application site. However, as a topically applied product, systemic effects are negligible and no clinically important drug-drug interactions have been identified. In vitro studies show that capsaicin does not inhibit or induce liver isoenzymes even at levels well above those found in blood samples of patients using the drug topically.¹⁶

Opioids

Opioids exert their effects by binding to opioid receptors, of which there are three types: mu, kappa, and delta. The majority of opioid-induced analgesia is thought to occur through agonism at mu-opioid receptors. Genetic variants of the opioid receptor mu-1 (OPRM-1) gene produce multiple mu-receptor subtypes, resulting in variable responses of individuals to mu-opioid agonists. While most available opioid analgesics (see Table 2) function as mu-opioid antagonists, some function as opioid agonist–antagonists or partial mu-opioid agonists.²⁹

The most commonly used mu-opioid agonists include morphine, fentanyl, hydromorphone, and oxycodone.²⁹ Methadone is an agonist at mu-opioid receptors and also an antagonist at NMDA receptors. However, because of its complex pharmacokinetics and unique safety considerations, methadone should only be used by experienced practitioners and is outside the scope of this program.

All mu-opioid agonists are equally effective analgesics when used at equivalent doses. Differences in opioid potency are responsible for higher or lower milligram amounts of particular opioids being required to achieve an equianalgesic effects in comparison with other opioids. Selection of a mu-opioid agonist should be made based on drug- and patient-specific factors such as desired dosage form, cost, and end-organ function. For example, morphine-3-glucuronide (M3G) is a metabolite of morphine which is renally cleared, and its accumulation is thought to cause adverse effects such as myoclonus and agitation. Patients with renal dysfunction are thus at higher risk of these adverse effects and would benefit from selection of an opioid without renally cleared metabolites, such as fentanyl or oxycodone. Hydromorphone is another alternative for patients with renal dysfunction because while it does have renally cleared metabolites, they are present in lower concentrations than M3G.²⁹

In contrast, morphine generally does not require dose adjustments in patients with mild liver disease, unlike oxycodone and fentanyl transdermal patches, both of which should be initiated at lower doses and used cautiously in patients with liver impairment.¹⁶

Of note, transmucosal, sublingual, and intranasal formulations of fentanyl — such as the lozenge (Actiq), buccal tablet (Fentora), buccal film (Onsolis), intranasal spray (Lazanda), sublingual tablet (Abstral), and sublingual spray — (Subsys) are approved by FDA only for use in opioid-tolerant patients for the management of breakthrough cancer pain; outpatient use is limited to patients and prescribers enrolled in the Transmucosal Immediate Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy program. The transdermal formulation of fentanyl is approved by FDA for the management of pain in opioid-tolerant patients for whom other analgesics are ineffective, and is not approved for the management of short-term, breakthrough pain. Opioid-tolerant is defined by the FDA to be patients receiving treatment with opioids at the following doses for at least 1 week: oral morphine 60 mg/d, transdermal fentanyl 25 mcg/h, oral oxycodone 30 mg/d, oral hydromorphone 8 mg/d, oral oxymorphone 25 mg/d, or oral hydrocodone 60 mg/d.¹⁶

Abuse-deterrent opioids are those agents formulated with a least one characteristic that makes misusing the opioid less desirable (see Table 3). The FDA requires pharmacokinetic studies comparing the opioid with and without the abuse-deterrent formulation, as well as randomized, double-blind, clinical studies comparing drug “likability” among recreational users for manufacturers to include claims of abuse deterrence in the products’ labeling.³⁰

After FDA approval, manufacturers of abuse-deterrent opioid formulations are required to conduct postmarketing studies to evaluate reductions in opioid misuse and adverse outcomes.³⁰ Although reformulation of some opioids to include abuse-deterrent properties, such as OxyContin, has been associated with a reduction in the abuse and diversion of the product, it has also been associated with an increase in the abuse of other opioids, such as heroin.³¹

Abuse-deterrent opioid formulations are significantly more costly than generic, non-abuse-deterrent opioid formulations and are not covered by all insurers. While abuse-deterrent opioids are certainly part of an opioid harm-reduction strategy, their increased cost relative to other prescription opioids and their potential to shift use to illicit opioids mean they are certainly not sufficient to solve the problem of opioid misuse and its associated harms.

Practitioners should proactively monitor for and manage opioid adverse effects. Common adverse effects associated with opioids include constipation, nausea and vomiting, sedation, and itching.²⁹

Opioid-induced constipation is particularly common and severe, affecting approximately 45% of patients receiving opioids, and causing one-third of patients to skip or reduce opioid doses due to constipation.³² Unlike other opioid adverse effects, tolerance to opioid-induced constipation does not develop. The condition should be proactively managed with a laxative given with opioid therapy. In addition to traditional laxatives, newer, targeted agents have been developed and are approved by FDA specifically for the management of opioid-induced constipation. While a review of these agents is outside the scope of this program, they are typically reserved for patients who do not respond to traditional laxatives due to their increased cost.

Respiratory depression is the most severe and life-threatening opioid adverse effect. Patients should be carefully monitored for sedation, particularly during the 3 to 5 days after opioid initiation or dose increase, as excessive sedation can be a precursor to respiratory depression.

OPIOID RISK MITIGATION

Before Initiating Opioid Therapy

Before initiating opioid therapy, practitioners should review realistic therapy goals and expectations with patients, and establish that opioid therapy will only be continued if the benefits of therapy are likely to outweigh the risks.⁶ Practitioners should also determine whether patients are appropriate candidates for opioid therapy by proactively assessing the risk of opioid misuse.⁶ Several evidence-based and validated tools are available, including the Screener and Opioid Assessment for Patients with Pain–Revised (SOAPP-R), which can be used before initiating opioid therapy.³³ The CDC guideline for use of opioids in chronic pain also recommends conducting a urine drug screen (UDS) before initiating opioid therapy, and considering use of UDS periodically during therapy to assess for the presence of prescribed opioids and the absence of illicit opioids.⁶

FDA has implemented a risk evaluation and mitigation strategy (REMS) that applies to all opioids (immediate-release and extended-release/long-acting agents) used on an outpatient basis. This Opioid Analgesic REMS program replaces the previous Extended-Release and Long-Acting Opioid Analgesic REMS. The new program requires opioid manufacturers to provide funding for development of continuing education courses based on the FDA’s Education Blueprint for Health Care Providers Involved in the Treatment and Monitoring of Patients with Pain. While healthcare professionals are not required to complete these continuing education programs, they are available for all healthcare providers involved the use and monitoring of outpatient opioid analgesics.³⁴

Selecting Opioid Therapy

Clinicians should consider several factors in selecting a specific opioid product for a patient. Therapy should not be initiated with long-acting or extended-release opioid formulations, and opioids should be used at the lowest effective dose for the shortest duration possible. The CDC guideline for opioid use in chronic pain recommends particular caution be exercised when the total daily opioid dose exceeds 50 morphine milligram equivalents (MME), while doses above 90 MME should be avoided and carefully justified if used. The risk of respiratory depression is significantly increased when opioids are used concomitantly with benzodiazepines; for this reason, every effort should be made to avoid concurrent use of these agents.⁶

Restricting the quantity of opioids prescribed to the number required for treatment is another important tool to ensure opioid safety and prevent diversion. The 2016 National Survey on Drug Use and Health found that among patients who misused prescription opioids, more than half reported obtaining the opioid from a friend or relative, and most reported being given the drug for free.³⁵ A 2018 study conducted by Seamans and colleagues found a small but statistically significant increase in risk of prescription opioid use among patients living in a household with someone treated with prescription opioids.³⁶ To mitigate the risk of unused opioids being diverted, practitioners should prescribe only the quantity of opioids reasonably expected to be necessary and should encourage patients to dispose of unused opioids immediately and appropriately.

Monitoring Opioid Therapy

During opioid therapy, practitioners should use validated tools to regularly assess patients for signs of opioid misuse. An example of such a tool is the Pain Medication Questionnaire.³⁷ Prescription drug monitoring programs (PDMPs) are another tool available to providers to assess a patient’s use of controlled substances. PDMPs should be reviewed before starting an opioid and at least quarterly during opioid therapy to ensure patients are not using controlled substances from multiple providers.⁶ Other monitoring strategies include performing pill counts and conducting regular face-to-face office visits.^33,38

Opioid treatment agreements are written agreements between providers and patients setting forth the responsibilities of both parties and the conditions under which opioids will be prescribed. These agreements may be particularly useful for patients receiving long-term opioid therapy or those thought to be at high risk of medication misuse.³⁸

Providing Naloxone

Clinicians should consider coprescribing naloxone for patients receiving high-dose opioids, or those at high risk of overdose because of concomitant drug therapy (i.e., benzodiazepines or other central nervous system depressants) or comorbid disease states (i.e., sleep apnea, chronic obstructive pulmonary disease).⁶ Providing naloxone to family members or community members and training them in its use has been shown to decrease opioid overdose deaths.³⁹

To sustain gains made in reduction of overdose deaths through increased naloxone availability, increased access to treatment for opioid use disorder is imperative.⁴⁰ As part of its Pain Strategy, the National Institutes of Health (NIH) has focused on improving access to naloxone by collaborating with private partners in the development of an easy-to-administer nasal formulation of naloxone. In addition, NIH is supporting research and development of longer-acting formulations of naloxone; these will be particularly useful for reversal of long-acting opioids.⁴¹

SUMMARY

The general approach to pain management should include a determination of whether pain acute or chronic in nature and caused by nociceptive or neuropathic mechanisms. Understanding the time course and pathophysiology of pain, in combination with analgesic pharmacology is essential when designing a safe and effective pain management regimen.

REFERENCES

1. Nahin RL. Estimates of pain prevalence and severity in adults: United States, 2012. J Pain. 2015;16(8):769-780.
2. McQuay HJKE, Moore RA, eds. Epidemiology of chronic pain. Seattle: IASP Press; 2008.
3. Dubois MY, Follett KA. Pain medicine: the case for an independent medical specialty and training programs. Acad Med. 2014;89(6):863-8.
4. Gomes T, Tadrous M, Mamdani M, et al. The burden of opioid-related mortality in the United States. JAMA Network Open. 2018;1(2):e180217.
5. Cicero TJ, Ellis MS, Kasper ZA. Increased use of heroin as an initiating opioid of abuse. Addict Behav. 2017;74:63-66.
6. Powell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain – United States, 2016. JAMA. 2016.315(15):1624-1645.
7. Blondell RD, Azadfard M, Wisniewski AM. Pharmacologic therapy for acute pain. Am Fam Phys. 2013;87(1):766-772.
8. Mills S, Torrance N, Smith BH. Identification and management of chronic pain in primary care: a review. Curr Psychiatry Rep. 2016;18:22.
9. McPherson ML, Cimino NM. Topical NSAID formulations. Pain Med. 2013;14:S35-S39.
10. Derry S, Wiffen PJ, Kalso EA, et al. Topical NSAIDs for acute and chronic pain in adults – an overview of Cochrane Reviews. Cochrane Database Syst Rev. 2017(65):CD008609.
11. Moor RA, Wiffen PJ, Derry S, et al. Non-prescription (OTC) oral analgesics for acute pain – an overview of Cochrane reviews. Cochrane Database Syst Rev. 2015;11:CD010794.
12. Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations. Lancet Neurol. 2015;14(2):162-173.
13. Krebs EE, Gravely A, Nugent S, et al. Effect of opioid vs nonopioid medications on pain-related function in patients with chronic back pain or hip or knee osteoarthritis pain: the SPACE randomized clinical trial. JAMA. 2018;319(9):872-882.
14. Moore P. The Pain Toolkit. https://www.paintoolkit.org. 2018. Accessed September 5, 2018.
15. Candido KD, Perozo OJ, Knezevic NN. Pharmacology of acetaminophen, nonsteroidal antiiflammatory drugs, and steroid medications: implications for anesthesia or unique associated risks. Anesthesiol Clin. 2017;35(2):e145-e162.
16. U.S. Food and Drug Administration. Drugs@FDA: FDA Approved Drug Products. Product labeling for individual drugs and drug products. 2018. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm. Accessed September 5, 2018.
17. Athersuch TJ, Antoine DJ, Boobis AR, et al. Paracetamol metabolism, hepatotoxicity, biomarkers and therapeutic interventions: a perspective. Toxicol Res. 2018;7(3):347-357.
18. Pawlosky N. Cardiovascular risk: are all NSAIDs alike? Can Pharm J (Ott). 2013;146(2):80-83.
19. Freedberg DE, Kim LS, Yang YX. The risks and benefits of long-term use of proton pump inhibitors: expert review and best practice advice from the American Gastroenterological Association. Gastroenterology. 2017;152(4):706-715.
20. Gwee KA, Goh V, Lima G, et al. Coprescribing proton-pump inhibitors with nonsteroidal anti-inflammatory drugs: risks versus benefits. J Pain Res. 2018;11:361-374.
21. Yuan JQ, Tsoi KK, Yang M, et al. Systematic review with network meta-analysis: comparative effectiveness and safety of strategies for preventing NSAID-associated gastrointestinal toxicity. Aliment Pharmacol Ther. 2016;43(12):1262-1275.
22. Scarpignato C, Gatta L, Zullo A, et al. Effective and safe proton pump inhibitor therapy in acid-related diseases: a position paper addressing benefits and potential harms of acid suppression. BMC Med. 2016;14:179.
23. Scarpignato C, Lanas A, Blandizzi C, et al. Safe prescribing of non-steroidal anti-inflammatory drugs in patients with osteoarthritis: an expert consensus addressing benefits as well as gastrointestinal and cardiovascular risks. BMC Med. 2015;13:55.
24. Curiel RV, Katz JD. Mitigating the cardiovascular and renal effects of NSAIDs. Pain Med. 2013;14:S23-S28.
25. Trelle S, Reichenbach S, Wandel S, et al. Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. BMJ. 2011;342:c7086.
26. Nissen SE, Yeomans ND, Solomon DH, et al. Cardiovascular safety of celecoxib, naproxen, or ibuprofen for arthritis. N Engl J Med. 2016; 2519:2529.
27. Schmidt M, Sorensen HT, Pedersen L. Diclofenac use and cardiovascular risks: series of nationwide cohort studies. BMJ. 2018;362:k3426.
28. Baron R, Binder A, Wasner G. Neuropathic pain: diagnosis, pathophysiological mechanisms, and treatment. Lancet Neurol. 2010;9:807-819.
29. Portenoy RK, Ahmed E. Principles of opioid use in cancer pain. J Clin Oncol. 2014;32(16):1662-1670.
30. The Medical Letter on Drugs and Therapeutics. Abuse-deterrent opioids. JAMA. 2019;319(19):2036-2037.
31. Curfman GD, Beletsky L, Sarpatwari A. Benefits, limitations, and value of abuse-deterrent opioids. 2018. JAMA Intern Med. 2018;178(1):131-132.
32. Bell TJ, Panchal SJ, Miaskowski C, et al. The prevalence, severity, and impact of opioid-induced bowel dysfunction: results of a US and European Patient Suvey (PROBE 1). Pain Med. 2009;10(1):35-42.
33. Sehgal N, Manchikanti L, Smith HS. Prescription opioid abuse in chronic pain: a review of opioid abuse predictors and strategies to curb opioid abuse. Pain Phys. 2012;15:ES67-ES92.
34. U.S. Food and Drug Administration. Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS). 2018. https://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm163647.htm. Accessed September 5, 2018.
35. Substance Abuse and Mental Health Service Administration. Key substance use and mental health indicators in the United States: Results from the 2016 National Survey on Drug Use and Health (HHS Publication No. SMA 17-5044, NSDUH Series H-52). Rockville, MD: Center for Behavioral Health Statistics and Quality, Substance Abuse and Mental Health Services Administration. 2017. https://www.samhsa.gov/data. Accessed September 5, 2018.
36. Seamans MJ, Carey TS, Westreich DJ, et al. Association of household opioid availability and prescription opioid initiation among household members. JAMA Intern Med. 2018;178(1):102-109.
37. Jones T, Moore T, Levy JL, et al. A comparison of various risk screening methods in predicting discharge from opioid treatment. Clin J Pain. 2012;28(2):93-100.
38. Jamison RN, Serraillier J, Michna E. Assessment and treatment of abuse risk in opioid prescribing for chronic pain. Pain Res Treat. 2011;941808.
39. McDonald R, Strang J. Are take-home naloxone programmes effective? Systematic review utilizing application of the Bradford Hill criteria. Addiction. 2016;111(7):1177-1187.
40. Adams JM. Increasing naloxone awareness and use: the role of health care practitioners. JAMA. 2018;319(20):2073-2074.
41. Volkow ND, Collins FS. The role of science in addressing the opioid crisis. N Engl J Med. 2017;377(4):391-394.

Back to Top