Lauren B. McKnight, PharmD, CPP

The management of acute and chronic pain often includes opioid therapy. In both the acute and chronic pain settings, however, opioids have several disadvantages including risk of nausea and vomiting, somnolence, constipation, respiratory depression, androgen deficiency, physical dependence, and tolerance. Opioid medications also carry a risk of abuse or addiction by either the patient or non-medical users. For these reasons, consideration of non-opioid strategies for pain management is beneficial. While opioids will certainly continue to have a place in pain management despite their disadvantages, the use of non-opioid medication options may limit the amount of opioid necessary or even result in improved pain control. In fact, given that the majority of both acute and chronic pain is thought to be complex and multifactorial, a multimodal analgesic approach is ideal for management. The purpose of this article is to review selected non-opioid medications used in either acute or chronic 

While oral and rectal acetaminophen have been available for quite some time, in 2010 an intravenous (IV) formulation was approved by the FDA. IV acetaminophen (Ofirmev) is indicated for use in management of mild to moderate pain and moderate to severe pain with adjunctive opioid analgesics.

 When studied as an adjunct to opioids following major surgery, IV acetaminophen demonstrated superiority over placebo in decreasing pain scores.

 IV acetaminophen has also been shown to decrease opioid consumption in major surgery by nearly one-third compared with placebo.

 The most common adverse effects seen with IV acetaminophen were constipation, nausea, injection site pain, pruritus, and vomiting.

 For adults and adolescents weighing greater than 50 kg, the recommended dosage of IV acetaminophen is 1000 mg every 6 hours or 650 mg every 4 hours, with a maximum single dose of 1000 mg.

 For adults and adolescents weighing under 50 kg as well as children ≥2 to 12 years old, the recommended dosing is 15 mg/kg every 6 hours or 12.5 mg/kg every 4 hours to a maximum of 75 mg/kg per day.

 As with other acetaminophen formulations, caution should be given to avoid exceeding the recommended maximum dose of 4000 mg per day to prevent potentially fatal hepatic injury. No benefit over oral or rectal acetaminophen has been demonstrated at this time; therefore use of IV acetaminophen would most likely be reserved for those patients who are unable to tolerate oral medications.

With ongoing drug shortage concerns with ketorolac,

 IV ibuprofen (Caldolor) may begin to see increased usage. Approved in 2009, IV ibuprofen is approved for management of mild to moderate pain and moderate to severe pain as an adjunct to opioid analgesics in adult patients.

 Similar to IV acetaminophen, IV ibuprofen has been shown to decrease pain scores and opioid usage in studies evaluating postoperative pain.

 The dosing for IV ibuprofen is 400 mg to 800 mg every 6 hours as necessary with a maximum of 3200 mg per day.

 The product must be diluted prior to administration and then infused over a period of 30 minutes, which is a disadvantage compared with ketorolac, which is available in prefilled syringes and single-dose vials for IV push or IM administration. Like all other non-steroidal anti-inflammatory drugs (NSAIDs), caution should be used when considering use of IV ibuprofen in patients with heart failure, kidney impairment, and those with a history of gastrointestinal bleeding, due to risk of serious cardiovascular and gastrointestinal events. Of note, IV ibuprofen is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft surgery.

 Compares with ketorolac, which is limited to a usage of 5 days, IV ibuprofen does not have a limit on duration of use, although one would expect this formulation to be limited to time periods when patients are unable to tolerate oral medications. An important medication safety consideration is the availability of another ibuprofen formulation for injection, ibuprofen lysine, for use in the closure of patent ductus arteriosus in premature infants. Given the differing indications and dosing between these 2 IV formulations of ibuprofen, inadvertent substitution of these products could result in patient harm. Another important safety concern to note is that in September 2012, Cumberland Pharmaceuticals, the manufacturer of IV ibuprofen, issued a statement recommending that only Baxter Viaflex and Hospira 250 mL bags be used when diluting the product due to reports received indicating possible incompatibility with B Braun PAB, Hospira VisIV , and Baxter AVIVA bags.

As noted above, a multimodal approach to 

t is often considered ideal, especially in the setting of chronic pain, where use of long-term opioids can increase the risk of many medication-related problems. Below, several non-opioid medication options for use in both nociceptive and neuropathic pain are reviewed.

 and pregabalin (Lyrica) have established efficacy and are typically considered first-line medications in various types of neuropathic pain.

 Gabapentin is initially started at a lower dose (300 to 600 mg per day) to limit side effects such as drowsiness and dizziness and titrated as tolerated to an effective dosage typically considered to be between 1800 and 3600 mg per day. In 2011 a once-daily gabapentin formulation (Gralise) was approved.

 This product was intended to overcome the dose-limiting side effects of drowsiness and dizziness often seen with regular-release gabapentin by allowing for plasma levels to peak overnight. Currently the once-daily gabapentin formulation is approved for the management of postherpetic neuralgia and has a recommended dose titration to reach a daily dose of 1800 mg within 2 weeks.

 There is no evidence that the once-daily gabapentin formulation confers better tolerability compared with regular-release gabapentin; however, it may be a reasonable option in patients who are unable to reach effective doses of regular-release gabapentin due to side effects. Other anticonvulsants such as lamotrigine, lacosamide, topiramate, carbamazepine, oxcarbazepine, and valproic acid have been studied in the setting of neuropathic pain but are typically considered only when patients have failed multiple other agents due to their limited evidence.

Serotonin and norepinephrine reuptake inhibitors

Duloxetine (Cymbalta) is FDA approved for management of diabetic peripheral neuropathy, fibromyalgia, and chronic musculoskeletal pain.

 A desirable effect of duloxetine in the setting of chronic pain is thought to be improvement in depression. Duloxetine is typically dosed for painful conditions as 30 mg once daily and then titrated to 60 mg once daily after 1 week if tolerated.

 The most common adverse effect seen with duloxetine is nausea.11 Due to reported cases of hepatic failure with use of duloxetine, its use in patients with hepatic impairment or alcohol abuse is not recommended.

 Venlafaxine has also demonstrated efficacy in the setting of diabetic peripheral neuropathy

 and is available generically, whereas duloxetine is still available only as a brand-name medication.

Tricyclic antidepressants such as amitriptyline, desipramine, and nortriptyline have shown benefit in the setting of postherpetic neuralgia, 

 These agents are often preferred due to low cost; however, their use may be limited by their anticholineric side effects (xerostomia, constipation, urinary retention) and potential for cardiac toxicity. Because of these potential side effects, caution is advised for use in elderly patients. A desirable effect of these agents is improvement in depression and sleep disruption, common problems among chronic pain patients. Amitriptyline, desipramine, and nortriptyline are all initially dosed as 25 mg at bedtime and increased by 25 mg every 3 to 7 days as tolerated to a maximum of 150 mg at bedtime.9 TCAs used in the setting of chronic pain are typically increased until pain is adequately controlled or side effects occur. As with many agents used in chronic pain, an adequate trial with TCAs is considered to be several weeks.

Various formulations of topical diclofenac are available, including Voltaren gel, Pennsaid solution, and Flector patch, and are used in the setting of osteoarthritis or musculoskeletal pain. In clinical practice, these agents are often considered when there is a contraindication to oral NSAID therapy, such as cardiovascular disease, kidney impairment, or history of gastrointestinal bleed, as the systemic absorption of diclofenac with these formulations is low. For example, the amount of diclofenac that is systemically absorbed from Voltaren gel is on average 6% of the systemic exposure from an oral form of diclofenac.

 Voltaren gel is approved for the relief of the pain of osteoarthritis of joints such as the knees and those of the hands but was not evaluated for use on joints of the spine, hip, or shoulder.13 Recommended dosing for Voltaren gel is 4 grams to the affected area 4 times daily on joints of the lower extremities and 2 grams to the affected area 4 times daily to joints of the upper extremities.

 Pennsaid is indicated for management of osteoarthritis of the knees only and its recommended dose is 40 drops on each painful knee 4 times a day.

 Flector patch is dosed as 1 patch to painful area twice daily and is indicated for acute pain due to minor strains, sprains, and contusions.

 No direct comparison between the various topical diclofenac formulations has been performed and in clinical practice choice of an agent is often left to patient preference of a particular dosage formulation: gel, solution, or patch.

Dr. McKnight is a clinical pharmacist at the University of North Carolina Hospitals Pain Management Center in Chapel Hill, North Carolina

Ofirmev [package insert]. San Diego, CA: Cadence Pharmaceuticals, Inc; 2010.

Sinatra RS, Jahr JS, Reynolds LW, Viscusi ER, Groudine SB, Payen-Champenois C. Efficacy and safety of single and repeated administration of 1 gram intravenous acetaminophen injection (paracetamol) for pain management after major orthopedic surgery. 

Memis D, Inal M, Kavalci G, Sezer A, Sut N. Intravenous paracetamol reduced the use of opioids, extubation time, and opioid-related adverse effects after major surgery in intensive care unit. 

Caldolor [package insert]. Nashville, TN: Cumberland Pharmaceuticals; 2009.

Singla N, Rock A, Pavliv L. A multi-center, randomized, double-blind placebo-controlled trial of intravenous-ibuprofen (IV-ibuprofen) for treatment of pain in post-operative orthopedic adult patients. 

Kroll PB, Meadows L, Rock A, Pavliv L. A multicenter, randomized, double-blind, placebo-controlled trial of intravenous ibuprofen (IV-ibuprofen) in the management of postoperative pain following abdominal hysterectomy. 

Caldolor. Cumberland Pharmaceuticals, Inc, website. Accessed December 14, 2012.

Dworkin R, O’Connor AB, Backonja M, et al. Pharmacologic management of neuropathic pain: evidence-based recommendations. 

Gralise [package insert]. Menlo Park, CA: Depomed Inc; 2012.

Cymbalta [package insert]. Indianapolis, IN: Eli Lilly and Company; 2012.

Sindrup SH, Otto M, Finnerup NB, Jensen TS. Antidepressants in the treatment of neuropathic pain. 

Voltaren gel [package insert]. Chadds Ford, PA: Endo Pharmaceuticals, Inc; 2009.

Pennsaid [package insert]. Mansfield, MA: Covidien; 2010.

Flector patch [package insert]. Mission, KS: Pfizer Inc; 2011.

Articles

Given the disadvantages of opioids, including side effects and potential for addiction, non-opioid medications play an important role in pain management.

Pain Management: Non-Opioid Medications

	ST is a 54-year-old woman with chronic neck pain related to severe cervical stenosis. Over the past several months, she has undergone unsuccessful trials with various long-acting opioids. Her pain clinic physician is now interested in pursuing a trial of methadone. What information should be ascertained prior to starting methadone? What education can the clinic-based pharmacist provide the patient regarding methadone use?

	Methadone is an opioid agonist indicated for the treatment of moderate-to-severe pain as well as detoxification or maintenance treatment of opioid addiction. It is not uncommon for chronic pain patients to initially have a negative connotation of methadone, as it is often thought of only for its role in opioid addiction. An important aspect of patient education in the setting of pain management is providing reassurance that methadone is indeed indicated for the treatment of chronic pain.

	In addition to the typical adverse effects associated with opioid therapy, including sedation, respiratory depression, and constipation, methadone poses risk of QTc interval prolongation which may result in torsade de pointes. A 2009 guideline, published by an independent physician panel, recommends that all patients being considered for methadone be warned of the potential for arrhythmias and questioned regarding history of structural heart disease, syncope, or arrhythmias. It is recommended to measure the QTc interval by electrocardiogram prior to starting methadone, within 30 days of methadone initiation, and annually thereafter. A QTc interval greater than 500 milliseconds is justification for considering methadone discontinuation, dose decrease, or elimination of factors that predispose to arrhythmias, such as electrolyte abnormalities. A QTc interval of 450 to 500 milliseconds warrants a thorough discussion of the risks and benefits of methadone therapy and more frequent electrocardiogram monitoring. 1 More frequent electrocardiogram monitoring for a QTc interval of 450 to 500 milliseconds was not defined by the guideline; however, a reasonable approach is to monitor every 6 months or following dose increases.

	Patients should be warned regarding the potential for serious drug interactions with methadone, which may increase the risk of respiratory depression or QTc prolongation. Since methadone is a CYP3A4 substrate, CYP3A4 inhibitors may increase plasma methadone concentrations and increase the risk of respiratory depression. Agents that prolong the QTc interval, such as tricyclic antidepressants, levofloxacin, and atypical antipsychotics, may further increase the risk of serious QTc interval prolongation. Patients should notify all health care providers considering new prescription or over-the-counter medications so appropriate evaluation for interactions is performed.

	Because of the variable and long elimination half-life of methadone, patients should be instructed not to exceed their prescribed dose, as significant drug accumulation may cause fatal respiratory depression.

	1. Krantz MJ, Martin J, Stimmel B, Mehta D, Haigney MC. QTc interval screening in methadone treatment. 

Dr. McKnight is a clinical pharmacist at the University of North Carolina Hospitals Pain Management Center in Chapel Hill, North Carolina.