Guidelines

Appendix B – Non-Opioid Pharmacology

Acetaminophen

Acetaminophen is an analgesic that may be used initially for the treatment of mild chronic pain or to augment other agents in treating mild to moderate pain. It lacks anti-inflammatory effects but is generally well tolerated at therapeutic doses. It does not damage the gastric mucosa but may have chronic renal- or hepatic-adverse effects (American Pain Society, 2008). Dosage should be restricted to a maximum of 4,000 mg per 24 hours, including acetaminophen contained in combination opioid products such as hydrocodone with acetaminophen. Acetaminophen should be used cautiously or avoided in patients with liver impairment.

Names of medications: Tylenol and various over-the-counter (OTC) products.

Indications

• Acetaminophen is an analgesic that may be used for the treatment of mild to moderate acute or chronic pain or to augment other agents.

Mechanism of action

• Has a central analgesic effect, with unknown mechanism. Possibly through inhibition of prostaglandin synthesis and elevation of the pain threshold.

Common adverse events

• Low incidence of GI effects, possible renal toxicity and liver toxicity associated with high-dose, long-term use.
• FDA recommends a maximum of 4,000 mg in 24 hours, including acetaminophen in combination opioid products.
• Lower dose limits of 2,000-3,000 mg daily for elderly, hepatically impaired patients, alcoholics and patients on other hepatotoxic medications.

Contraindications

• Use cautiously or avoid in patients with liver toxicity.

Anticonvulsants

Anticonvulsants have been used for the treatment of pain for over 50 years. Most of the evidence to support the use of anticonvulsants in pain management is for treatment of neuropathy and fibromyalgia. Mechanisms of action for the anticonvulsants differ and are not fully understood in relation to analgesic effect. In general, the class has a significant risk of side effects and requires frequent monitoring by the prescribing provider. Use in certain populations, such as the geriatric population, should be done with caution and with close follow-up.

Names of medications: Carbamazepine, gabapentin, lamotrigene, oxcarbazepine, sodium valproate, and pregabalin

Indications

• Trigeminal neuralgia
  - Carbamazepine (Vargas-Espinosa, 2012; Goodyear-Smith, 2009)
  - Oxcarbazepine
  - Lamotrigine (Goodyear-Smith, 2009)

• Fibromyalgia
  - Pregabalin (Wiffen, 2013)
  - Gabapentin
  - Lacosamide not beneficial (Hearn, 2012)
  - Phenytoin not beneficial (Birse, 2012)

• Diabetic peripheral neuropathy
  - Pregabalin (Griebeler, 2014; Wiffen, 2013; Moore, 2011; Goodyear-Smith, 2009)
  - Gabapentin (Griebeler, 2014; Wiffen, 2013; Goodyear-Smith, 2009)
  - Oxcarbazepine
  - Carbamazepine (Griebeler, 2014; Goodyear-Smith, 2009)
  - Sodium valproate (Goodyear-Smith, 2009)

• Post-herpetic neuralgia
  - Pregabalin (Wiffen, 2013; Goodyear-Smith, 2009)
  - Gabapentin (Wiffen, 2013; Vargas-Espinosa, 2012, Goodyear-Smith, 2009)
  - Carbamazepine (Goodyear-Smith, 2009)
  - Sodium valproate (Goodyear-Smith, 2009)

• Painful HIV-associated neuropathy
  - Lamotrigine (Goodyear-Smith, 2009)
  - Gabapentin (Goodyear-Smith, 2009)

• Complex regional pain syndrome type I
  - Lamotrigine (McCleane, 2000)

• Neuropathic pain associated with spinal cord injuries
  - Pregabalin (Snedecor, 2013; Goodyear-Smith, 2009)
  - Gabapentin (Goodyear-Smith, 2009; Kroenke, 2009b)

• Pain in patients with Guillain-Barre syndrome
  - Carbamazepine (Goodyear-Smith, 2009)
  - Gabapentin (Goodyear-Smith, 2009)

• Acute and chronic pain
  - Lamotrigine not beneficial (Wiffen, 2007)

• Polyneuropathy
  - Levetiracetam not beneficial (Holbech, 2011)
  - Phenytoin not beneficial (Birse, 2012)

General mechanism

• Pregabalin and gabapentin modulate the alpha2delta subunit of the N-type voltage-gated calcium channels, regulating the influx of calcium into the nerve and reducing the outflow of excitatory neurotransmitters that transmit pain.
• Phenytoin analgesic properties seem to be related to its membrane-stabilizing action.
• Carbamazepine prevents repeated discharges in neurons.
• Sodium valproate and clonazepam are thought to work through enhancement of GABA inhibitory system.

Common adverse events

Nausea, vomiting, diarrhea, hyponatremia (carbamazepine, oxcarbazepine), rash, pruritis, weight gain, edema, dry mouth.

Contraindications

• Bone marrow depression, with or within 14 days of monoamine oxidase (MAO) inhibitor use (carbamazepine).
• Use of NNRTIs (phenytoin).
• Hepatic disease or significant impairment, urea cycle disorders, pregnant women for prevention of migraines, known mitochondrial disorders (valproate).
• Recent alcohol use (within six hours), patient with metabolic acidosis or taking metformin (topiramate).

Monitoring parameters

• Carbamazepine: Complete blood count (CBC) with differential, reticulocytes, serum iron, lipid panel, liver function tests, urinalysis, blood urea nitrogen (BUN), serum carbamazepine levels, thyroid function tests, serum sodium when initiating or changing doses.
• Lamotrigine: Serum levels of concurrent anticonvulsants, liver function tests (LFTs), renal function when initiating or changing doses.
• Oxcarbazepine: Serum sodium, thyroid labs and CBC.

Antidepressants

Tricyclic antidepressants (TCAs), serotonin norepinephrine reuptake inhibitors (SNRIs) and to a lesser extent selective-serotonin reuptake inhibitors (SSRI) have a role in the treatment of pain, especially if the patient has co-existing insomnia, anxiety or depression. Antidepressants may provide pain relief independent from their antidepressant effects, since analgesic effects occur earlier and at lower doses compared to antidepressant effects. TCAs are very effective in the treatment of neuropathic pain; however, side effects including significant anticholinergic properties may limit their use in specific populations. Evidence continues to grow to support the use of SNRIs in neuropathic pain, and now that a few of the agents are available generically, their use in clinical practice for pain management has expanded greatly in the past few years.

Names of medications: Amitriptyline, bupropion, doxepin, imipramine, nortriptyline, despiramine, venlafaxine, desvenlafaxine, duloxetine, milnacipran

Indications

• Diabetic peripheral neuropathy
  - Duloxetine (Griebeler, 2014; Kroenke, 2009b)
  - Venlafaxine (Griebeler, 2014)
  - Nortriptyline (Griebeler, 2014)
  - Amitriptyline (Griebeler, 2014)

• Fibromyalgia
  - Duloxetine (Arnold, 2004)
  - Venlafaxine (Arnold, 2004)
  - Milnacipran (Gendreau, 2005; Vitton, 2004)

• Neuropathic pain
  - Buproprion (Semenchuk, 2001)
  - Venlafaxine (Sindrup, 2003)
  - Duloxetine (Arnold, 2004)

• Painful physical symptoms
  - Duloxetine (Robinson, 2013; Romera, 2012; Gaynor, 2011a; Gaynor, 2011b; Perahia, 2009; Brecht, 2007)

General mechanism

• Bupropion inhibits reuptake of norepinephrine and dopamine.
• Duloxetine and venlafaxine inhibit serotonin and norepinephrine reuptake, and are a weak inhibitor of dopamine reuptake.
• Milnacipran, amitriptyline, nortriptyline, doxepin, imipramine and despiramine inhibitor of norepinephrine and serotonin reuptake and potentiation of descending inhibitory pathways.

Common adverse events

Elevated blood pressure, nausea, dry mouth, insomnia, drowsiness, constipation, fatigue, dizziness, orthostatic hypotension (TCAs).

Contraindications

• Tricyclic antidepressants are contraindicated in patients with patients with severe cardiac disease (specifically conduction disturbances) and severe gastrointestinal dysfunction.
• Bupropion is contraindicated in patients with seizure disorders and history of anorexia/bulimia.
• Duloxetine is contraindicated in patients with uncontrolled glaucoma.
• Recommend avoiding TCAs in older adults due to the risk of anticholinergic side effects.

Monitoring parameters

• Blood pressure should be checked prior to initiating therapy and on regular basis.
• BUN/Creatinine.
• LFTS (SNRIs).
• Heart rate, blood pressure and electrocardiogram (ECG) in older adults and patients with preexisting cardiac disease (TCAs).

Glucocorticosteroids

Glucocorticoids are adrenalcortical steroids that have potent anti-inflammatory properties and are used primarily in rheumatic disorders and other acute inflammatory diseases. Glucocorticoids can be administered orally or by injection, including epidural injections, injection into facet joints, the sacroiliac space and intra-articular injections (see the “Interventional Treatment” section). In rheumatoid arthritis, they reduce joint tenderness and pain more than NSAIDs, but benefits must be weighed against significant adverse effects associated with chronic use.

Names of medications: Oral dexamethasone, hydrocortisone, prednisone, and long-acting injectable suspensions, methylprednisolone and Triamcinolone.

Indications: As adjunctive therapy for:

• Rheumatoid arthritis
• Osteoarthritis
• Bursitis
• Synovitis
• Epicondylitis using Iontophoresis treatment (Nirschl, 2003)
• Lateral epicondylitis using iontophoresis and phonophoresis of naproxen are equally effective (Baskurt, 2003)

General mechanism

• Reduce inflammation by suppression of polymorphonuclear leucocytes.
• Suppression of the immune system by reducing activity and volume of the lymphatic system.

Common adverse events: Are dose dependent and associated with chronic use. Low incidence of adverse effects in doses comparable to prednisone 5 mg daily with increasing incidence in doses of 10-15 mg or higher. Adverse effects include GI bleed, hyperglycemia, increased infections, osteoporosis, and increased skeletal fractures and mood disorders.

Monitoring parameters

• With chronic use monitor blood glucose, white blood cells, and watch for other signs and symptoms associated with adverse effects (GI, CNS changes) (Micromedex).

Muscle Relaxants and Antispasmodics

Skeletal muscle relaxant may be useful along with analgesics for the short-term management of muscle spasms and pain. There is mixed evidence supporting the use of these medications for long-term use. Some medications including benzodiazepines and carisoprodol are centrally acting and carry the risk of physical dependence. Muscle relaxants are more beneficial for acute short-term use and are not recommended for chronic use.

Names of medications: Baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, dantrolene, metaxalone, methocarbamol, orphenadrine and tizanidine.

Indications

• Peripheral musculoskeletal conditions: Muscle relaxants include antispasmodic agents used to treat spasms.

• Acute low back pain: The American Pain Society and the American College of Physicians recommend reserving skeletal muscle relaxants as an optional alternative treatment for acute low back pain, with acetaminophen and NSAIDs as first-line agents. This recommendation is based on available literature, which shows skeletal muscle relaxants are better than placebo but not more effective than NSAIDs in patients with acute back pain (Chou, 2007).

• Chronic back pain: A recommendation from the Cochrane review is that skeletal muscle relaxers may provide some benefit, but there is little evidence to support their use as the standard of treatment for chronic back pain. Additionally, these studies demonstrate the efficacy of skeletal muscle relaxers for up to 14 days after symptom onset, and evidence for long-term use is lacking. Other studies suggest treatment with these medications is less than a month (Chou, 2007).

• Fibromyalgia
  - A meta-analysis evaluating the use of cyclobenzaprine showed that, although this medication was better than placebo for the treatment of fibromyalgia, it was considered inferior to antidepressants.
  - Tizanidine is a muscle relaxant that may be used for longer periods of time due to its alpha-2 sympathomimetic mechanism of action, but it may cause hypotension. It may provide benefits as an adjunct in the treatment of fibromyalgia.
  - Cyclobenzaprine has shown benefits in the treatment of fibromyalgia at doses of 10 to 40 mg daily (Tofferi, 2004). It is a tricyclic amine and has side effects similar to the tricyclic antidepressants, including drowsiness/dizziness, dry mouth and an increased risk for arrhythmias. Concurrent use of cyclobenzaprine with tricyclic antidepressants is not contraindicated, but patients should be monitored for the potential increase in these related adverse effects.

• Spasticity including multiple sclerosis, spinal cord injury, traumatic brain injury, cerebral palsy and post-stroke syndrome
  - Botulinim toxin A in combination with physical and occupational therapy improves functional outcomes in these conditions.
  - Baclofen, dantrolene and tizanidine are FDA approved.
  - Benzodiazepines, dantrolene, and baclofen have been used to treat spasticity in cerebral palsy but are generally less useful than botulinum toxin.
  - Intrathecal baclofen administered via a pump achieves higher cerebrospinal fluid drug levels as compared with oral administration. Intrathecal baclofen may be effective in reducing spasticity in severely affected patients, but its use is also associated with substantial complications.
  - Antispasticity agents used to decrease spasticity (increased tone or contractions of muscles causing stiff or awkward movements as a result of an upper motor neuron damage) in neurological disorders.

• Muscle spasms: Evidence for the use of tizanidine comes from a Cochrane review, which showed that the combination of tizanidine plus analgesics provided better pain relief and a decrease in muscle spasms compared to analgesics alone (Van Tulder, 2003).

• Lancinating, paroxysmal neuropathic pain: Baclofen may have benefits in the treatment (Cherkin, 1998; Borenstein, 1990).

Mechanism of action

• Cyclobenzaprine is a tricyclic amine with undefined mechanism of action.
• Tizanidine is an alpha adrenergic agonist with undefined mechanism of action.
• Carisoprolol is metabolized to mebrobamate, a central acting depressant.
• Injection of botulinum toxin type A into affected muscles blocks the presynaptic release of acetylcholine from motor endplates of the lower motor neuron at the myo-neural junction and decreases tone by limiting muscle contraction.

Common adverse events

Drowsiness/dizziness, dry mouth and hypotension (more common with tizanidine). Some medications such as benzodiazepines and carisoprodol are centrally acting and carry the risk of physical dependence.

Non-Steroidal Anti-inflammatory Drugs (NSAIDs)

NSAIDs are indicated for the treatment of mild to moderate inflammatory or non-neuropathic pain. In general, NSAIDs should be used for periodic flare-ups rather than for long-term chronic use. NSAIDs have significant opioid dose-sparing properties and in turn may reduce opioid-related side effects. Use of NSAIDs should be monitored closely due to the class risk of cardiovascular, gastrointestinal and renal adverse effects. This is in alignment with the recommendations made by the American Society of Nephrology as part of the Choosing Wisely® campaign, and additional information can be found at http://www.choosingwisely.org/societies/american-society-of-nephrology/.

Names of medications: Aspirin, salsalate, naproxen, ibuprofen, ketoprofen, flurbiprofen, oxaprozin, diclofenac, etodolac, indomethacin, tolmetin, sulindac, meloxicam, piroxicam, meclfenamate, mefenamic acid, nabumetone and celecoxib.

Indications

• Acute – Periodic use for mild to moderate inflammatory or non-neuropathic pain (tendonitis, bursitis, dysmenorrhea, gout, headaches, low back pain)
  - Ketoprofen (Wong, 2016; Friedman, 2015; Sarzi-Puttini, 2013)
  - Diclofenac (Dietrich, 2014; Daniels, 2012)

• Chronic – Osteoarthritis, rheumatoid arthritis (Colebatch, 2012; Kroenke, 2009b)

General mechanism

• Peripheral inhibition of the enzyme cyclooxygenase (COX), which plays a central role in inflammatory conditions, as well as an effect on the central nervous system.

Common adverse events

Platelet inhibition, dyspepsia, gastric ulceration, nephrotoxicity, hepatotoxicity, confusion.

Contraindications

• Patients with renal insufficiency, GI bleeding, platelet dysfunction, reduced cardiac output, difficult to control hypertension, hypovolemia, hyponatremia, aspirin-sensitive asthma or cirrhosis.
• Recommended to avoid use in older adults. (American Society of Nephrology as part of the Choosing Wisely® campaign)

Monitoring parameters

• CBC
• Periodic liver function tests
• Renal function (urine output, serum BUN/creatinine)

Topical Therapies

Topical NSAIDs can provide acceptable levels of pain relief in knee and hand osteoarthritis, and are available through a diclofenac 0.3% topical patch and 1% topical gel. Topical formulations provide more localized pain relief with efficacy comparable to oral products. They generally have a lower incidence of GI adverse effects compared with oral NSAIDs. Topical NSAID GI adverse effects did not differ from placebo but were less frequent than with oral NSAIDs (Derry, 2012).

Capsaicin, the active ingredient in the herbal product cayenne, is used topically to deplete the pain mediator substance-P from afferent nociceptive neurons. Topical creams and solutions have been used in treating both neuropathic pain and arthritic pain. Capsaicin should be applied for at least six weeks to see full benefits. The side effect of local burning is common, and most patients become tolerant after a few days (Mason, 2004; Devers, 2000).

Names of medications: Capsacin, lidocaine patches and ointment, and diclofenac gel and patch.

Indications

• Neuropathic and arthritic pain, diabetic neuropathy, post-herpetic neuralgia.
  - Capsaicin topical creams and solutions have been used (Fusco, 1997; Treatment of Painful Diabetic Neuroplasty with Topical Capsaicin, 1991).
  - Lidocaine in the form of an ointment or a patch (Rowbotham, 1995).
  - Topical lidocaine 5% patches are FDA approved for post-herpetic neuralgia.
  - Topical lidocaine 5% patches are FDA approved for post-herpetic neuralgia and have shown efficacy in other neuropathic pain syndromes. Systemic absorption of lidocaine is minimal, and the patch has a clean safety profile with the correct dosage schedule.
  - Topical NSAIDS are approved for and provide acceptable pain relief in knee and hand osteoarthritis.

Mechanism of action

• Capsaicin, the active ingredient in the herbal product cayenne, is used topically to deplete the pain mediator substance-P from afferent nociceptive neurons. It deactivates local C-polymodal nociceptors at the vanilloid receptor.
• Topical NSAIDs inhibit the enzyme cyclooxygenase resulting in reduce formation of prostaglandins, thromboxanes and prostacyclin.

Common adverse events

Dermatitis and other local reactions are usually not severe. Topical NSAID GI adverse effects did not differ from placebo but were less frequent than with oral NSAIDs (Derry, 2012). Capsaicin products have local burning.

Contraindications

• NSAIDs should be avoided in patients who have experienced asthma, urticaria or other allergic reactions to aspirin or other NSAID’s.