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10 Articles in Volume 15, Issue #10
2015 Has Been a Good Year for Clinical Progress
Addison’s Original 1855 Cases Reveal Stories of Chronic Pain
Can We Prevent Chronic Pain?
Letters to the Editor: Nerve Fiber Testing, Fibromyalgia
Medication Guide for Pain—A Short Primer for Primary Care
Odd Pet Behavior During SCS Trial—Case Report
Opioid-Induced Constipation: New and Emerging Therapies—Update 2015
Palliative Care: Dying With Dignity
PPM Editorial Board: Year in Pain Management 2015
QT Intervals and Antidepressants

Medication Guide for Pain—A Short Primer for Primary Care

This review briefly discusses each category of pain medications and provides a table that can be used as a reference tool during rounds or office visits.

There are several classes of medications available for the treatment of chronic, noncancer pain, depending on the classification, duration, and severity of pain a patient is experiencing.

Nociceptive pain, which is pain in muscles, joints, or tissues that occurs due to injury, is typically described as dull, aching, or throbbing. In contrast, neuropathic pain, which involves abnormal signaling in the nerves as a result of injury or damage to the brain, spinal cord, or the peripheral nerves, is usually described as sharp, burning, tingling, or numbing.

Acute pain is defined as pain that lasts less than 3 months and is associated with an identifiable cause, whereas chronic pain may or may not have an identifiable cause, lasts beyond the typical course of an illness or injury (usually 6 months or less), and negatively impacts a patient’s quality of life.1 Chronic pain can be a mixture of both nociceptive and neuropathic pain.

Medications can help reduce pain, but they may not be able to eliminate it. Medications also are associated with adverse events (AEs) that can negatively impact a patient’s quality of life. Each patient’s response to and tolerance of a pain medication is unique, and use of certain pain medications may be limited or even contraindicated due to a patient’s comorbidities, concurrent medications, and renal and/or hepatic impairment.

Therefore, medications are recommended as a component of an interdisciplinary approach to chronic pain management with continual re-evaluation of the risks and benefits of continued use.2

Patients should be counseled about realistic expectations related to potential pain relief, possible AEs, expected duration of therapy (some medications may need to be initiated at doses below the therapeutic level and gradually titrated to minimize AEs), and plans for discontinuation due to intolerable AEs, lack of adequate response, or aberrant behaviors when applicable.

The medications used for chronic, noncancer pain management are broadly classified as non-opioids, adjuvants, topical analgesics, muscle relaxants, and opioids (Table). Download 'Selected Medications Used in Pain Management' table as a PDF.



Non-Opioids

Non-opioid medications, such as acetaminophen (Tylenol, others), aspirin (Bayer, Bufferin, others), and non-steroidal anti-inflammatory drugs (NSAIDs), are indicated for the treatment of mild to moderate nociceptive pain. For acute, subacute, and chronic low back pain, both acetaminophen and NSAIDs can be recommended, in addition to self-care and non-pharmacologic therapies such as cognitive behavioral therapy, exercise, massage, and yoga.2

Acetaminophen

Acetaminophen is available both over-the-counter (OTC) and as a prescription in combination with opioids. For adults, acetaminophen can be taken 4 to 6 times a day as long as the total amount taken per day does not exceed 3,000 mg due to risk of liver toxicity.1 Under the supervision of a prescriber, up to 4,000 mg of acetaminophen can be taken per day. However, patients with chronic liver disease should be prescribed lower maximum doses (2,000 mg/d). Since hundreds of OTC products contain acetaminophen, it is important for patients to keep track of the total daily amount ingested from all sources.3

Acetaminophen is not recommended for patients with a history of alcohol abuse, and patients should not consume alcohol while using acetaminophen. Patients also should avoid acetaminophen if they have a history of phenylketonuria.4

Aspirin and NSAIDs

Unlike acetaminophen, aspirin and NSAIDs have anti-inflammatory properties and are used widely for arthritis, low back pain, and other musculoskeletal disorders. Aspirin and select NSAIDs, such as ibuprofen (Advil, Motrin, others) and naproxen (Aleve, Naprosyn, others), are available OTC, whereas the majority of NSAIDs require a prescription.

NSAID use should be limited to the lowest dose and shortest duration due to the risk of gastric distress, ulceration, bleeding, increased risk of cardiovascular events, and kidney toxicity. To address these concerns, pharmaceutical companies have been investigating new delivery systems. Recently, Iroko Pharmaceuticals has gained approval of three new formulations of NSAIDs that use "SoluMatrix Fine Particle Technology" that contains submicron particles of the NSAID that are approximately 10 times smaller than their original size. This smaller particle size provides an increased surface area, leading to faster dissolution, thus "allowing clinicins to prescribe the lowest effective dose of NSAIDs for the shortest possible duration," noted the company. The three new products include Vivlodex (meloxicam), Zorvolex (diclofenac) and Tivorbex (indomethacin).

Up to 25% of chronic NSAID users will develop ulcer disease and 2% to 4% will have a gastrointestinal (GI) bleed or perforation.4 Strategies to decrease GI risk include prescribing a proton-pump inhibitor or misoprostol (Cytotec, others) along with the NSAID, or prescribing the cyclooxygenase-2 (COX-2)–selective NSAID celecoxib (Celebrex).3

However, patients taking antiplatelet therapy, such as low-dose aspirin for cardioprotection, should consult their provider prior to initiating an NSAID regimen, especially a COX-2 inhibitor, because chronic NSAID use can diminish aspirin’s cardioprotective effects, which can increase the risk of cardiovascular events. Providers should evaluate patients for cardiovascular and GI risk prior to initiating an NSAID for chronic pain management.

Adjuvant Pain Treatments

Medications that are indicated for the treatment of other conditions have also been studied for the treatment of chronic neuropathic pain—for example antidepressants and anticonvulsants.

Antidepressants

Tricyclic antidepressants (TCAs), including amitriptyline (formerly sold as Elavil), desipramine (Norpramin, others), and nortriptyline (Pamelor, others), were the first antidepressants recommended for treatment of chronic pain conditions, including diabetic neuropathy, post-herpetic neuralgia, migraine prophylaxis, and subacute or chronic low back pain.2,5-7

An adequate trial of an antidepressant for chronic pain occurs over 4 to 8 weeks at a therapeutic dose. Unfortunately, many patients are unable to tolerate TCAs due to their dose-related anticholinergic AEs, including sedation, constipation, urinary retention, blurry vision, and dry mouth.

TCAs should be used with caution in elderly patients because they may increase the risk of falls. Patients with a history of cardiac disease also should be cautious because TCAs increase the risk of QT prolongation. Practitioners should obtain a baseline electrocardiogram for patients aged older than 40 years and limit the TCA dose to less than 100 mg per day if possible.5

The newer antidepressant agents, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), may be a better option for some patients because they are not associated with anticholinergic AEs.

The evidence for the use of SSRIs in neuropathic pain is conflicting, and their use generally is limited to patients who have failed therapy with other antidepressants.8

The SNRI antidepressants that have been shown to be effective for chronic pain include venlafaxine (formerly sold as Effexor), duloxetine (Cymbalta, Irenka, others), and milnacipran (Savella). Venlafaxine is recommended for the treatment of diabetic neuropathy but not post-herpetic neuralgia.5,6

Studies have shown that venlafaxine can be effective for polyneuropathies as well as for migraine prophylaxis.7 Studies with duloxetine have focused on its use as a primary treatment of chronic muscoskelatal pain, such as low back pain and pain due to osteoarthritis, as well as diabetic neuropathy and fibromyalgia,1,5,7 whereas milnacipran has mainly been studied for the treatment of fibromyalgia.

The most common AE associated with duloxetine is nausea, which can be minimized with a 1-week titration to the target dose. Duloxetine is contraindicated in patients with creatinine clearance less than 30 mL/min or severe hepatic impairment. Venlafaxine should be used with caution in patients with cardiovascular disease due to its associated risk of cardiac conduction abnormalities; it can also cause dose-dependent increases in blood pressure, which should be monitored during therapy.

Since chronic pain and mood are directly related, many patients with chronic pain already are taking mood stabilizers, so it is important for practitioners to evaluate for potential drug-drug interactions prior to the initiation of an antidepressant for chronic pain.

Anticonvulsants

Anticonvulsants, such as gabapentin (Gralise, Horizant, Neurontin, others) and pregabalin (Lyrica), also are recommended as first-line treatments for neuropathic conditions such as diabetic neuropathy, postherpetic neuralgia, and fibromyalgia.1,5,6 Both anticonvulsants are generally well tolerated. The common AEs associated with these agents include sedation, dizziness, dry mouth, weight gain, and edema, with pregabalin carrying a warning that it should be used with caution in patients with Class III and IV heart failure. Both medications are started low and titrated as tolerated to target doses to minimize these AEs. Both also have to be dose adjusted for renal impairment. Pregabalin is classified as a schedule V medication, indicating that it is associated with a risk of misuse and dependence.

Other anticonvulsants used for chronic pain include valproic acid (Depakene, Stavzor, others) for diabetic neuropathy and migraine prophylaxis, and carbamazepine (Carbetrol, Tegretol, others), which is first-line treatment for trigeminal neuralgia.1,6,7

Both require routine liver function tests and complete blood counts for the duration of therapy due to risk of thrombocytopenia (valproic acid) and various anemias (carbamazepine). Patients taking carbamazepine also should be monitored routinely for electrolyte imbalances, renal issues, skin reactions, thyroid abnormalities, and eye effects. Carbamazepine is a potent CYP450 3A4 enzyme inducer that is associated with many drug-drug interactions.

Patients initiated on an anticonvulsant for pain should be monitored closely for changes in behavior, including suicidal thoughts or signs and symptoms of depression.

Topical Analgesics

Topical analgesics are available in various formulations (creams, gels, sprays, liquid, patches, and balms OTC) for the treatment of mild to moderate pain. Topical analgesics can be applied several times a day to the affected area, with care taken to avoid any wounds, damaged skin, and sensitive areas. Practitioners should counsel patients to wash their hands after application. Salicylate is an active ingredient in some topical analgesics that reduces pain and inflammation.

Diclofenac (Voltaren, Solaraze, others) is available as a prescription topical gel for the treatment of knee osteoarthritis. Counter-irritants, such as menthol salicylate, menthol, and camphor, are used for mild to moderate musculoskeletal pains associated with strains, sprains, back pain, arthritis, and bruises.1

Capsaicin cream is used for both neuropathic pain and arthritis (osteoarthritis or rheumatoid arthritis).1,6 Since its active ingredient is derived from hot peppers and it can cause skin irritation and burning, clinicians should counsel patients to apply it with gloves and wash their hands after appying it. Capsaicin (Qutenza) also is available as an 8% patch for the treatment of post-herpetic neuralgia. The patch must be applied in a physician’s office so the patient can be observed for response and tolerance.

Lidocaine 5% patch (Lidoderm) also is FDA-approved for the treatment of post-herpetic neuralgia and is recommended for treatment of localized allodynia.1,5 Up to 3 patches may be applied in one sitting for up to 12 hours and the patches may be cut to fit.

Muscle Relaxants

Skeletal muscle relaxants frequently are used as adjunctive medication in the treatment of acute low back pain. Their use in chronic pain is more limited. Muscle relaxants are divided into 2 categories—antispastics and antispasmodics.

Antispastic agents are used for the treatment of multiple sclerosis or cerebral palsy, but there is limited evidence for their use in the treatment of musculoskeletal conditions. Muscle relaxants with antispasmodic properties, including cyclobenzaprine (Amrix, Fexmid, others), metaxalone (Skelaxin, others), methocarbamol (Robaxin, others), and tizanidine (Zanaflex, others), can be used for the short-term treatment (up to 2 weeks) of acute pain, such as acute low back pain in patients not responding to acetaminophen or NSAIDs.2,9

All muscle relaxants can cause dizziness and sedation. Cyclobenzaprine is structurally similar to TCAs and may have a similar mechanism of action and AEs; it has been studied for use in low back pain and fibromyalgia.9 Carisoprodol (Soma, others) is a schedule IV controlled substance because it is converted to meprobamate, a barbiturate-like drug that can cause both psychological and physical dependence. Because of this, many pain clinicians no longer recommend carisoprodol, especially for patients currently taking opioids.

Practitioners should select a muscle relaxant based on its side effect profile, abuse potential, potential interactions, and patient-specific information because there is limited evidence about the long-term use of muscle relaxants for chronic pain as well as a lack of data comparing muscle relaxants.

Tramadol

Tramadol (ConZip, Ultram, others) is a short-acting analgesic that has weak activity at the opioid receptor. It also works as a SNRI similar to the antidepressants previously discussed. Opioids are DEA schedule II to III controlled substances due to their risk for psychological and physical dependence, but tramadol was recently reclassified as schedule IV substance.10

The dose of tramadol must be adjusted for renal and hepatic impairment, and it should not be used in patients with a history of a seizure disorder. Also, use of tramadol in patients already on other serotonergic medications can increase the risk for serotonin syndrome.

Opioids

Practitioners should reserve opioids for the treatment of moderate to severe chronic pain after exhausting non-opioid and non-pharmacologic therapies with better benefit to risk ratios.11 Opioids bind to receptors in the brain and spinal cord to block the transmission of pain signals from the periphery, changing the patient’s perception of pain.

Opioids are available as short-acting formulations either alone (eg, hydromorphone [Dilaudid, others], morphine [Duramorph, others], and oxycodone [Roxicodone, others]) or in combination with non-opioids including acetaminophen or NSAIDs (eg, codeine/acetaminophen, hydrocodone/acetaminophen [Lorcet, Vicodin, others], or oxycodone/acetaminophen [Percocet, Roxicet, others]). Long-acting formulations of opioids include buprenorphine (Butrans), fentanyl (Duragesic, Ionsys, others), hydrocodone (Hysingla, Zohydro), hydromorphone (Exalgo) morphine (Kadian, MS Contin, others), methadone (Dolophine, others), oxycodone (OxyContin, others), oxymorphone (Opana) and tapentadol (Nucynta).

Unlike acetaminophen or NSAIDs, which have a maximum daily dose, opioids do not have a ceiling dose. However, recently a number of states have set target doses, which if exceeded trigger an evaluation by a pain specialist.12 The dose is limited by associated AEs, such as sedation, cognitive impairment, respiratory depression, constipation, nausea, and vomiting.

Patients may develop tolerance to these AEs over time, except for constipation, which will occur throughout the duration of opioid therapy. It is important for a patient on chronic opioid therapy to have a prophylactic bowel regimen consisting of a stimulant laxative (eg, senna, bisacodyl, or polyethylene glycol) with or without a stool softener, for example docusate sodium, to minimize constipation and prevent bowel obstruction. Clinicians should counsel patients to avoid bulk-forming laxatives, such as psyllium, which can cause bowel impaction.

Opioids have been shown to decrease pain scores in patients with osteoarthritis, neuropathic pain, and chronic low back pain, but the majority of studies conducted in this setting were of short duration (up to 12 weeks) and used doses up to 180 mg morphine equivalents per day, with mixed results regarding impact on patient function.13

Chronic opioid therapy also has been associated with the development of long-term AEs such as hormonal changes (testosterone depletion, decreases in libido, hypogonadism, and infertility), immunosuppression, falls and fractures in elderly patients, QT prolongation (with use of methadone), worsening or development of sleep apnea, and abnormal pain sensitivity leading to hyperalgesia, in addition to the risk of addiction.13-16

Chronic opioid therapy also has contributed to increases in emergency room visits, hospitalizations due to nonfatal overdoses, and deaths from accidental overdose.15 The risk of accidental overdose and death increases when higher doses of opioids are used and when opioids are combined with other sedating medications, such as benzodiazepines or sedative hypnotics.

The use of long-term opioid therapy is controversial, given the lack of evidence for long-term effectiveness, improvement in patient functionality, and the risk of long-term AEs.13-15

Guidelines recommend that practitioners obtain informed consent in the form of a pain management agreement from the patient that outlines treatment expectations, goals of therapy as established by the patient, potential risks of chronic opioid therapy, alternatives, and patient and provider responsibilities during the course of therapy.11 Clinicians also should assess patients regularly for the four As of pain medicine: Analgesia, Activity, Adverse effects, and Aberrant behaviors.17 The frequency of assessment is determined by risk stratification.

Summary

Medication management is just one component in an interdisciplinary treatment approach to chronic pain. Providers should discuss the risks and benefits of treatment and establish realistic expectations with their patients prior to initiating a medication trial. Subsequent monitoring should assess changes in pain severity, effects on patient’s functionality, progress toward patient-defined goals, AEs, adherence to the recommended treatment plan (both pharmacologic and non-pharmacologic), and the development of aberrant behaviors when applicable. Therapy should be re-evaluated periodically, and tapered and discontinued if goals are not met, intolerable AEs occur, or aberrant behaviors persist.

Acknowledgements
The authors thank all the veterans and providers who contributed to the Pain Education School program. The authors also thank the Jesse Brown VA Medical Center and the Anesthesiology/Pain Clinic department for their vision and ongoing support of the Pain Education School program.

Last updated on: October 30, 2017
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