Contents part 1: Introduction




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Recommended frequency and duration of treatment:

  1. Time to Produce Effect: Immediate.

  2. Frequency: 1 to 2 times per week.

  3. Optimum Duration: 6 weeks.

  4. Maximum Duration: 2 months. (Colorado, 2006) At 2 months, patients should be reevaluated. Care beyond 2 months may be indicated for certain chronic pain patients in whom massage is helpful in improving function, decreasing pain, and improving quality of life. In these cases, treatment may be continued at 1 treatment every other week until the patient has reached MMI and maintenance treatments have been determined. Extended durations of care beyond what is considered “maximum” may be necessary in cases of re-injury, interrupted continuity of care, exacerbation of symptoms, and in those patients with comorbidities. Such care should be re-evaluated and documented on a monthly basis. Treatment beyond 2 months should be documented with objective improvement in function. Palliative care should be reevaluated and documented at each treatment session. Injured workers with complicating factors may need more treatment, if functional improvement is documented by the treating physician

Medical foods

Medical foods and dietary supplements are not recommended for treatment of chronic pain as they have not been shown to produce meaningful benefits or improvements in functional outcomes. FDA defines a medical food as “a food which is formulated to be consumed or administered enterally under the supervision of a physician and which is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements, based on recognized scientific principles, are established by medical evaluation.” There are no quality studies demonstrating the benefit of medical foods in the treatment of chronic pain. Medical foods (defined in section 5(b)(3) of the Orphan Drug Act, 21 U.S.C. 360ee(b)(3)), are exempted from the labeling requirements for health claims and nutrient content claims under the Nutrition Labeling and Education Act of 1990 (see 21 U.S.C. 343 (q) (5) (A) (iv)). Medical foods do not have to be registered with the FDA. (CFSAN, 2008)

Medical marijuana

See Cannabinoids.

Medications for acute pain (analgesics)

Recommended as indicated below.

Acetaminophen is the initial choice for treatment of acute pain & acute exacerbations of chronic pain in a dose of 1,000 mg. A recent study found that in a single dose, aspirin was similar to acetaminophen (mg to mg comparison) for treatment of acute pain, although aspirin is more likely to produce GI side effects. (Edwards, 2006) (Sachs, 2005) To help encourage appropriate acetaminophen use, the makers of Extra Strength Tylenol® (acetaminophen) have implemented new dosing instructions lowering the maximum daily dose from 4,000 mg to 3,000 mg. (McNeil, 2012) There should be caution about daily doses of acetaminophen and liver disease if over 4,000 mg per day or in combination with other NSAIDs. (Watkins, 2006) A 2008 Cochrane review found that NSAIDs are not more effective than acetaminophen for acute low-back pain, but acetaminophen had fewer side effects, which support recommending NSAIDs as a treatment option after acetaminophen. (Roelofs-Cochrane, 2008)

NSAIDs are superior to acetaminophen for some types of pain, and can provide analgesia similar to opioids in some settings, including post-operatively. (Mason, 2006) An important concern is side effects such as GI disturbance, renal dysfunction, increased edema, and increased blood pressure. NSAIDs, and the Cox-2 NSAIDS in particular, also are associated with thrombotic cardiovascular events.

Opioids: Refer to the DWC “Guideline for the Use of Opioids to Treat Work-Related Injuries” for recommendations on the use of opioids.

Medication overuse headache

Definition: (1) Headache present on ≥ 15 days a month; (2) Regular overuse for ≥ 3 months of acute treatment of symptomatic treatment drugs including opioids, combination analgesics, triptans or ergotamines (one or more of these drugs); (3) Use of these same medications on ≥ 15 days a month or a regular basis for ≥ 3 months (with no overuse of any one class alone); & (4) headache that is worse during medication overuse. The prevalence of this condition may be as high as 59-64% of patients seen in tertiary headache centers in the US. A risk factor for this condition is frequent to daily use of analgesics for chronic neck pain (RR=2.2) and chronic low back pain (RR=2.3). Other risks include the use of opioids for other medical conditions, psychiatric comorbidity, dependence on other psychoactive substances (including alcohol and nicotine), and a family history of substance abuse.

Recommended treatment: Includes screening for medication usage via the following: interviews with the patient; interviews with other family members; contact with prescribing physicians; and pharmacy billing records. Urine drug screens are also recommended. Complex cases may require both medical and behavioral intervention. (Lake, 2008) (Olesen, 2006)

Medrol dose pack

See Oral corticosteroids.

Mefenamic Acid (Ponstel®)

See NSAIDs (non-steroidal anti-inflammatory drugs); NSAIDs, GI symptoms & cardiovascular risk; NSAIDs, hypertension and renal function; & NSAIDs, specific drug list & adverse effects for general guidelines, as well as specific Mefenamic Acid (Ponstel®) listing for more information and references.

Melatonin

Recommended. See Insomnia treatment. There are also experimental and clinical data supporting an analgesic role of melatonin. In published studies melatonin shows potent analgesic effects in a dose-dependent manner, and melatonin has been shown to have analgesic benefits in patients with chronic pain. Also, the repeated administration of melatonin improves sleep and thereby may reduce anxiety, which leads to lower levels of pain. (Wilhelmsen, 2011)

Meloxicam (Mobic®)

Meloxicam is a nonsteroidal anti-inflammatory drug (NSAID) for the relief of the signs and symptoms of osteoarthritis. See NSAIDs (non-steroidal anti-inflammatory drugs); NSAIDs, GI symptoms & cardiovascular risk; NSAIDs, hypertension and renal function; & NSAIDs, specific drug list & adverse effects for general guidelines, as well as specific Meloxicam (Mobic®) listing for more information and references. A large systematic review of available evidence on NSAIDs confirms that naproxen and low-dose ibuprofen are least likely to increase cardiovascular risk. In the pooled analyses, meloxicam had a risk profile similar to that of ibuprofen and celecoxib. (McGettigan, 2011)

Meperidine (Demerol®)

Meperidine is an opioid analgesic, similar to morphine, and has been used to relieve moderate to severe pain. The AGS updated Beers criteria for inappropriate medication use includes meperidine. (AGS, 2012) Refer to the DWC “Guideline for the Use of Opioids to Treat Work-Related Injuries” for recommendations on the use of opioids.

Meprobamate

Meprobamate is the active metabolite of carisoprodol. See Carisoprodol (Soma®).

Metaxalone (Skelaxin®)

Recommended with caution as a second-line option for acute LBP and for short-term pain relief in patients with chronic LBP. Metaxalone (marketed by King Pharmaceuticals under the brand name Skelaxin®) is a muscle relaxant that is reported to be relatively non-sedating. See Muscle relaxants for more information and references.

Methadone



Refer to the DWC “Guideline for the Use of Opioids to Treat Work-Related Injuries” for recommendations on use. Methadone is used as a second-line drug for moderate to severe pain, only if the potential benefit outweighs the risk, unless methadone is prescribed by pain specialists with experience in its use and by addiction specialists, Pharmacokinetics and pharmacodynamics: Increased morbidity and mortality appears, in part, secondary to the long and variable half-life of the drug (8-59 hours; up to 110 hours in patients with cancer). Pain relief on the other hand only lasts from 4-8 hours. It may take several days to weeks to obtain adequate pain control. Genetic differences appear to influence how an individual will respond to this medication. Following oral administration, significantly different blood concentrations may be obtained. Vigilance is suggested in treatment initiation, conversion from another opioid to methadone, and when titrating the methadone dose. Frequent or large dose changes are generally not necessary after initial titration. If analgesia is lost, this may reflect the addition of a medication that affects metabolism. (Weschules 2008) (Fredheim 2008)

Adverse effects and mortality: Methadone-related deaths are noted to be increasing at a faster rate than other poisoning deaths using data from the National Center for Health Statistics, increasing by 468% from 1999 to 2005 (total poisoning deaths increased by 66%). Methadone-related poisoning deaths had the greatest percentage increase of deaths compared with other opioids, although the actual number of deaths is less than from other opioids or cocaine. The Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS®) System found that from 2003 until 2006 patients that filled prescriptions for methadone had the highest fatal poisoning rate for all people filling prescriptions. Approximately 35% of methadone deaths were characterized as resulting from an abuse situation. Two-thirds involved use of multiple drugs including antidepressants, alcohol and cocaine. Deaths can also occur with too rapid titration. Delayed adverse effects may occur due to methadone accumulation during chronic administration. (Fingerhut, 2008) (Dart, 2007) (Center for Substance Abuse Treatment, 2009) Systemic toxicity is more likely to occur in patients previously exposed to high doses of opioids. This may be related to tolerance that develops related to the NMDA receptor antagonism properties. Patients may respond to lower doses of methadone than would be expected based on this antagonism. One severe side effect is respiratory depression (which persists longer than the analgesic effect).

Abuse potential: Methadone does have the potential for abuse. “Street methadone” is primarily used for self-medication of detoxification and withdrawal symptoms. According to CDC, methadone has played a central role in the increase in overdose deaths from prescription painkillers. More than 30% of prescription painkiller deaths involve methadone, even though only 2% of painkiller prescriptions are for this drug. Six times as many people died of methadone overdoses in 2009 than a decade before. (CDC, 2012)

Cardiac safety and EKG monitoring: Methadone use is associated with an increased risk for QT prolongation and torsade de pointes (TdP). Patients who are at most risk for TdP include those on high daily methadone doses, those who take medications that cause QTc prolongation or inhibit CYP34A enzymes, and patients with electrolyte imbalances (low magnesium or potassium).

Methylnaltrexone (Relistor®)

Recommended only as a possible second-line treatment for opioid-induced constipation. See Opioid-induced constipation treatment.

Microcurrent electrical stimulation (MENS devices)

Not recommended. Based on the available evidence conclusions cannot be made concerning the effect of Microcurrent Stimulation Devices (MENS) on pain management and objective health outcomes. MENS is characterized by sub-sensory current that acts on the body's naturally occurring electrical impulses to decrease pain and facilitate the healing process. MENS differs from TENS in that it uses a significantly reduced electrical stimulation. TENS blocks pain, while MENS acts on the naturally occurring electrical impulses to decrease pain by stimulating the healing process. (BlueCross BlueShield, 2005)

Midazolam

Not recommended. See Benzodiazepines.

Milnacipran (Savella®)

Under study as a treatment for fibromyalgia syndrome. An FDA Phase III study demonstrated "significant therapeutic effects" of milnacipran for treatment of fibromyalgia syndrome. Milnacipran has been approved for the treatment of depression outside of the U.S. and is a dual serotonin- and norepinephrine-reuptake inhibitor (SNRI). (Rooks, 2007) Milnacipran, one of the pioneer serotonin and norepinephrine reuptake inhibitors (SNRIs), was designed from theoretic considerations to be more effective than selective serotonin reuptake inhibitors (SSRIs) and better tolerated than tricyclic antidepressants (TCAs). (Kasper, 2010) FDA has now approved milnacipran (Savella) for the management of fibromyalgia. Milnacipran should be prescribed with caution in patients with a history of seizure disorder, mania, or controlled narrow-angle glaucoma and should ordinarily not be prescribed in patients with substantial alcohol use or evidence of chronic liver disease. (FDA, 2009) As there is little to no evidence that the cause of fibromyalgia is related to industrial injuries, the use of Savella should be restricted to documented cases of fibromyalgia as part of an appropriate treatment plan.

Mindfulness meditation

See Yoga & Mindfulness meditation.

Mobic® (meloxicam)

Mobic is a brand name for meloxicam supplied by Boehringer Ingelheim Pharmaceuticals, Inc. See Meloxicam (Mobic®).

Modafinil (Provigil®)

Indications: Provigil is indicated to improve wakefulness in adult patients with excessive sleepiness associated with narcolepsy, obstructive sleep apnea, and shift work sleep disorder. Patients should have a complete evaluation with a diagnosis made in accordance with the International Classification of Sleep Disorders or DSM diagnostic classification. Adverse effects: This drug has been known to be misused and/or abused, particularly by patients that have a history of drug or stimulant abuse. Common adverse effects include headache, nausea, nervousness, rhinitis, diarrhea, back pain, anxiety, insomnia, dizziness, and dyspepsia. Dose: The standard dose for these conditions is 200 mg a day. The dose should be reduced to ½ for patients with severe hepatic impairment. (Clinical Pharmacology, 2008) (Micromedix, 2008) (Lexi-Comp, 2008) (AHFS Drug Information, 2008) Modafinil is increasingly being used as a cognitive enhancer. Although initially launched as distinct from stimulants that increase extracellular dopamine by targeting dopamine transporters, recent preclinical studies suggest otherwise. There is need for heightened awareness for potential abuse of and dependence on modafinil. (Kumar, 2008) (Volkow-JAMA, 2009) Prescriptions for modafinil have rapidly increased in recent years, and most of this increase is due to off-label use, according to a JAMA study, with 89% of patients prescribed modafinil not having an on-label diagnosis. The company that markets modafinil, Cephalon Inc, was sued by several US states for promoting modafinil for off-label indications and agreed to a settlement in 2008. (Peñaloza, 2013)

Monofilament testing

Not recommended. The sole use of monofilament testing is not recommended to diagnose peripheral neuropathy, according to the results of a recent systematic review. Several tests are used to detect peripheral neuropathy, including vibration perception, application of warmth and cold, and nerve conduction studies, which are assumed to be the reference standard. Electrodiagnostic tests can be complex, expensive, and time consuming, which hampers their widespread use, especially in primary care, where for most patients peripheral neuropathy is diagnosed and treated. Monofilament testing is an inexpensive, easy-to-use, and portable test for assessing the loss of protective sensation, and it is recommended by several practice guidelines to detect peripheral neuropathy in otherwise normal feet. Sensitivity of the 5.07/10-g monofilament to detect peripheral neuropathy ranged from 41% to 93%, and specificity ranged from 68% to 100%. Despite the frequent use of monofilament testing, little can be said about the test accuracy for detecting neuropathy in feet without visible ulcers. The diagnosis of peripheral neuropathy can be made only after a careful clinical examination with more than 1 test, as recommended by the American Diabetes Association. Tests for this clinical examination are vibration perception (using a 128-Hz tuning fork), pressure sensation (using a 10-g monofilament at least at the distal halluces), ankle reflexes, and pinprick. When in doubt, a nerve conduction test might be necessary to establish a firm diagnosis. (Dros, 2009)

Morphine

See specific Morphine sulfate (MS Contin®; Avinza®; Kadian®; Oramorph SR®) listing for more information and references, or by the brands: Avinza; Kadian & Oramorph. See DWC “Guideline for the Use of Opioids to Treat Work-Related Injuries,” Appendix F1, for dosing recommendations.

Morphine pumps

See Implantable drug-delivery systems/ Intrathecal drug delivery systems (IDDSs).

MS Contin®

See Morphine.

MSM (methylsulfonylmethane)

See CRPS, medications, DMSO.

Multidisciplinary pain programs

See Chronic pain programs.

Muscle relaxants (for pain)

See recommendations in specific DWC MTUS body part chapters. Muscle relaxants may be effective in reducing pain and muscle tension, and increasing mobility. Also there is no additional benefit shown in combination with NSAIDs. Efficacy appears to diminish over time, and prolonged use of some medications in this class may lead to dependence. (Schnitzer, 2004) (Van Tulder, 2004) (Airaksinen, 2006) Sedation is the most commonly reported adverse effect of muscle relaxant medications. These drugs should be used with caution in patients driving motor vehicles or operating heavy machinery. Drugs with the most limited published evidence in terms of clinical effectiveness include chlorzoxazone, methocarbamol, dantrolene and baclofen. (Chou, 2004) According to a recent review in American Family Physician, skeletal muscle relaxants are the most widely prescribed drug class for musculoskeletal conditions (18.5% of prescriptions), and the most commonly prescribed antispasmodic agents are carisoprodol, cyclobenzaprine, metaxalone, and methocarbamol, but despite their popularity, skeletal muscle relaxants should not be the primary drug class of choice for musculoskeletal conditions. (See2, 2008)

Classifications: Muscle relaxants are a broad range of medications that are generally divided into antispasmodics, antispasticity drugs, and drugs with both actions. (See, 2008) (van Tulder, 2006)

ANTISPASTICITY DRUGS: Used to decrease spasticity in conditions such as cerebral palsy, MS, and spinal cord injuries (upper motor neuron syndromes). Associated symptoms include exaggerated reflexes, autonomic hyperreflexia, dystonia, contractures, paresis, lack of dexterity and fatigability. (Chou, 2004)

Baclofen (Lioresal®, generic available): The mechanism of action is blockade of the pre- and post-synaptic GABAB receptors. It is recommended orally for the treatment of spasticity and muscle spasm related to multiple sclerosis and spinal cord injuries. Baclofen has been noted to have benefits for treating lancinating, paroxysmal neuropathic pain (trigeminal neuralgia, non-FDA approved). (ICSI, 2007)

Side Effects: Sedation, dizziness, weakness, hypotension, nausea, respiratory depression and constipation. This drug should not be discontinued abruptly (withdrawal includes the risk of hallucinations and seizures). Use with caution in patients with renal and liver impairment.

Dosing: Oral: 5 mg three times a day. Upward titration can be made every 3 days up to a maximum dose of 80 mg a day. (See, 2008)

Dantrolene (Dantrium®, generic available): Not recommended. The mechanism of action is a direct inhibition of muscle contraction by decreasing the release of calcium from the sarcoplasmic reticulum.



Side Effects: A black-box warning has been issued about symptomatic fatal or nonfatal hepatitis.

Dosing: 25 mg a day for 7 days, 25 mg three times a day for 7 days, 50 mg three times a day for 7 days and then 100 mg three times a day. (See, 2008)

ANTISPASMODICS: Used to decrease muscle spasm in conditions such as LBP although it appears that these medications are often used for the treatment of musculoskeletal conditions whether spasm is present or not. The mechanism of action for most of these agents is not known. (Chou, 2004)

Cyclobenzaprine (Flexeril®, Fexmid™, generic available, ER as Amrix®): Recommended for a short course of therapy. Immediate release (eg, Flexeril, generic) recommended over extended release (Amrix) due to recommended short course of therapy (also note substantial increase in cost for extended release without corresponding benefit for short course of therapy). Limited, mixed-evidence does not allow for a recommendation for chronic use. Cyclobenzaprine is a skeletal muscle relaxant and a central nervous system depressant with similar effects to tricyclic antidepressants (e.g. amitriptyline). Cyclobenzaprine is more effective than placebo in the management of back pain, although the effect is modest and comes at the price of adverse effects. It has a central mechanism of action, but it is not effective in treating spasticity from cerebral palsy or spinal cord disease. Cyclobenzaprine is associated with a number needed to treat of 3 at 2 weeks for symptom improvement. The greatest effect appears to be in the first 4 days of treatment. (Browning, 2001) (Kinkade, 2007) (Toth, 2004) See Cyclobenzaprine. Cyclobenzaprine has been shown to produce a modest benefit in treatment of fibromyalgia. Cyclobenzaprine-treated patients with fibromyalgia were 3 times more likely to report overall improvement and to report moderate reductions in individual symptoms (particularly sleep). A meta-analysis concluded that the number needed to treat for patients with fibromyalgia was 4.8. (ICSI, 2007) (Tofferi, 2004) A recent RCT found that time to relief was better with immediate release compared to extended release cyclobenzaprine. (Landy, 2011)

Side Effects: Include anticholinergic effects (drowsiness, urinary retention and dry mouth). Sedative effects may limit use. Headache has been noted. This medication should be avoided in patients with arrhythmias, heart block, heart failure and recent myocardial infarction. Side effects limit use in the elderly. (See, 2008) (Toth, 2004)

Dosing: 5 mg three times a day. Can be increased to 10 mg three times a day. This medication is not recommended to be used for longer than 2-3 weeks. (See, 2008)

Methocarbamol (Robaxin®, Relaxin™, generic available): The mechanism of action is unknown, but appears to be related to central nervous system depressant effects with related sedative properties. This drug was approved by the FDA in 1957.



Side Effects: Drowsiness, dizziness and lightheadedness.

Dosing: 1500 mg four times a day for the first 2-3 days, then decreased to 750 mg four times a day. (See, 2008)

Metaxalone (Skelaxin®, generic available) is reported to be a relatively non-sedating muscle relaxant. The exact mechanism of action is unknown, but the effect is presumed to be due to general depression of the central nervous system. Metaxalone was approved by the FDA in 1964 and data to support approval were published in the mid-1960s. (Toth, 2004)



Side Effects: Dizziness and drowsiness, although less than that compared to other skeletal muscle relaxants. Other side effects include headache, nervousness, nausea, vomiting, and GI upset. A hypersensitivity reaction (rash) has been reported. Use with caution in patients with renal and/or hepatic failure.

Dosing: 800 mg three to four times a day (See, 2008)

Chlorzoxazone (Parafon Forte®, Paraflex®, Relax™DS, Remular S™, generic available): this drug works primarily in the spinal cord and the subcortical areas of the brain. The mechanism of action is unknown but the effect is thought to be due to general depression of the central nervous system. Advantages over other muscle relaxants include reduced sedation and less evidence for abuse. (See, 2008)



Side Effects: Drowsiness and dizziness. Urine discoloration may occur. Avoid use in patients with hepatic impairment.

Dosing: 250-750 mg three times a day to four times a day.

Carisoprodol (Soma®, Soprodal 350™, Vanadom®, generic available): Not recommended in ODG. Suggested by the manufacturer for use as an adjunct to rest, physical therapy, analgesics, and other measures for the relief of discomfort associated with acute, painful musculoskeletal conditions. (AHFS, 2008) A 250 mg formulation was FDA approved in 9/07 for treatment of acute, painful musculoskeletal conditions such as backache. Neither of these formulations is recommended for longer than a 2 to 3 week period. Carisoprodol is metabolized to meprobamate an anixolytic that is a schedule IV controlled substance. Carisoprodol is classified as a schedule IV drug in several states but not on a federal level. It is suggested that its main effect is due to generalized sedation as well as treatment of anxiety. This drug was approved for marketing before the FDA required clinical studies to prove safety and efficacy. Withdrawal symptoms may occur with abrupt discontinuation. (See, 2008) (Reeves, 2003) For more details, see Carisoprodol, where it is “Not recommended.” See also Weaning, carisoprodol (Soma®).



Side Effects: drowsiness, psychological and physical dependence, & withdrawal with acute discontinuation.

Dosing: 250 mg-350 mg four times a day. (See, 2008)

Orphenadrine (Norflex®, Banflex®, Antiflex™, Mio-Rel™, Orphenate™, generic available): This drug is similar to diphenhydramine, but has greater anticholinergic effects. The mode of action is not clearly understood. Effects are thought to be secondary to analgesic and anticholinergic properties. This drug was approved by the FDA in 1959.



Side Effects: Anticholinergic effects (drowsiness, urinary retention, dry mouth). Side effects may limit use in the elderly. This medication has been reported in case studies to be abused for euphoria and to have mood elevating effects. (Shariatmadari, 1975)

Dosing: 100 mg twice a day; combination products are given three to four times a day. (See, 2008)

ANTISPASTICITY/ANTISPASMODIC DRUGS:



Tizanidine (Zanaflex®, generic available) is a centrally acting alpha2-adrenergic agonist that is FDA approved for management of spasticity. (Malanga, 2008)) One study (conducted only in females) demonstrated a significant decrease in pain associated with subacute and chronic myofascial pain syndrome and the authors recommended its use as a first-line option to treat myofascial pain. (Malanga, 2002) May also provide benefit as an adjunct treatment for fibromyalgia. (ICSI, 2007)

Side effects: somnolence, dizziness, dry mouth, hypotension, weakness, hepatotoxicity (LFTs should be monitored baseline, 1, 3, and 6 months). (See, 2008)

Dosing: 4 mg initial dose; titrate gradually by 2 – 4 mg every 6 – 8 hours until therapeutic effect with tolerable side-effects; maximum 36 mg per day. (See, 2008) Use with caution in renal impairment; should be avoided in hepatic impairment. Tizanidine use has been associated with hepatic aminotransaminase elevations that are usually asymptomatic and reversible with discontinuation. This medication is related to clonidine and should not be discontinued abruptly. Weaning should occur gradually, particularly in patients that have had prolonged use. (Zanaflex-FDA, 2008)

Benzodiazepines: Not recommended due to rapid development of tolerance and dependence. There appears to be little benefit for the use of this class of drugs over nonbenzodiazepines for the treatment of spasm. (See, 2008) See Benzodiazepines.

Myobloc

See Botulinum toxin.

Myofascial pain

Overview of this pain syndrome (not a procedure): Myofascial pain is defined as pain or autonomic phenomena referred from active trigger points, with associated dysfunction including restricted range of motion. The trigger point is a focus of hyperirritability in a palpable taut band of skeletal muscle that, when compressed, is locally tender and, if sensitized, gives rise to referred pain and tenderness. However, trigger points may be observed in up to 33-50% of adults in a general medicine practice according to the International Association for the Study of Pain. The pain quality is dull or achy and associated with autonomic changes (abnormal sweating, lacrimation, flushing and temperature changes). Active trigger points cause pain at either rest or activity. Latent trigger points are not painful but present with other signs, primarily restricted movement and weakness. The therapy for myofascial pain requires enhancing central inhibition through pharmacology or behavioral techniques and simultaneously reducing peripheral inputs through physical therapies including exercises and trigger point-specific therapy. Long-term clinical efficacy of most treatment for trigger points and myofascial pain has not been determined due to lack of research. (Graff-Radford, 2004) (Alvarez, 2002) (Borg-Stein, 2002

Myotherapy

See Massage therapy.

Nabilone (Cesamet®)

Recommended for treatment of chemotherapy-induced nausea, but not recommended for pain until there is better evidence. In a preliminary, placebo-controlled, 1-month trial, the marijuana-based synthetic drug nabilone (Cesamet, Valeant Pharmaceuticals) showed promise for temporary pain relief for fibromyalgia patients. Future studies with a longer duration of treatment and a stable dose are still needed. When interpreting the study results, it is important to note that the study drug was costly, the study was done in a small number of patients, and there was a high dropout rate. In addition, the dropout patients were not included in an intention-to-treat analysis, which would have resulted in a lower improvement rate. (Skrabek, 2008) Nabilone was approved in 1985 by the FDA for treatment of chemotherapy-induced nausea and vomiting that has not responded to conventional antiemetics. See also Cannabinoids.

Nabumetone (Relafen®)

See NSAIDs (non-steroidal anti-inflammatory drugs); NSAIDs, GI symptoms & cardiovascular risk; NSAIDs, hypertension and renal function; & NSAIDs, specific drug list & adverse effects for general guidelines, as well as specific Nabumetone (Relafen®) listing for more information and references.

Naloxone (Narcan®)

See also Buprenorphine for chronic pain; Opioids: Refer to the DWC “Guideline for the Use of Opioids to Treat Work-Related Injuries” for more information. See also Propoxyphene (Overdose).

FDA has approved a handheld auto-injector for use by caregivers to deliver a single dose of naloxone to reverse suspected opioid overdose. Evzio (naloxone hydrochloride injection, Kaleo, Inc) can be carried in a pocket or stored in a medicine cabinet and is intended for the emergency treatment of known or suspected opioid overdose, characterized by decreased breathing or heart rates, or loss of consciousness. Naloxone rapidly reverses the effects of opioid overdose and is the standard treatment for overdose, but existing naloxone drugs require administration via syringe and are most commonly used by trained medical personnel in emergency departments and ambulances. (FDA, 2014)



Naltrexone (Vivitrol® extended-release injectable suspension)

On Oct. 12, 2010, the FDA approved Vivitrol to treat and prevent relapse after patients with opioid dependence have undergone detoxification treatment. Vivitrol is an extended-release formulation of naltrexone administered by intramuscular injection once a month. Naltrexone works to block opioid receptors in the brain. It blocks the effects of drugs like morphine, heroin, alcohol, and other opioids. (FDA, 2010) A study in The Lancet concluded that extended-release (ER) naltrexone (Vivitrol), a receptor antagonist, is a safe and effective option for treating opioid dependence disorder (ODD). Those who received once-monthly injections of ER naltrexone had significantly more opioid-free weeks during a 6-month period and fewer cravings than those who received placebo. Methadone and buprenorphine are opioid agonists that have previously been shown to be effective for managing ODD. Naltrexone, on the other hand, is a µ-opioid receptor antagonist. It has a differentiated mechanism of action that blocks opioid receptors in the brain, producing no euphoria or sedation and generating no physical opioid dependence. Vivitrol offers an antagonist or nonaddictive, nonopioid option. The once-a-month administration helps to ensure patient compliance and that therapeutic concentrations of the medication are maintained. (Krupitsky, 2010) Continued use of once-monthly extended-release naltrexone intramuscular injection (Vivitrol) is a safe and effective method of preventing relapse to opioid dependency after detoxification. It significantly increased the number of abstinence weeks (90% vs 35% for placebo) and the likelihood of total abstinence (36% vs 23%). (Krupitsky, 2011) See also Embeda (morphine sulfate & naltrexone hydrochloride).

Naproxen (Naprosyn®, EC-Naprosyn®, Anaprox®, Anaprox DS®, Aleve® [otc], Naprelan®)

Recommended as an option. Naproxen is a nonsteroidal anti-inflammatory drug (NSAID) for the relief of the signs and symptoms of osteoarthritis. See NSAIDs (non-steroidal anti-inflammatory drugs); NSAIDs, GI symptoms & cardiovascular risk; NSAIDs, hypertension and renal function; & NSAIDs, specific drug list & adverse effects for general guidelines, as well as specific Naproxen (Naprosyn®, EC-Naprosyn®, Anaprox®, Anaprox DS®, Aleve® [otc], Naprelan®) listing for more information and references. See also Anti-inflammatory medications.

Narcotics

Refer to the DWC “Guideline for the Use of Opioids to Treat Work-Related Injuries” for information and recommendations;

Nausea

See Antiemetics (for opioid nausea).

Nerve blocks

See Intravenous regional sympathetic blocks (for RSD, nerve blocks).

Nerve conduction studies (NCS)

See Electrodiagnostic testing (EMG/NCS).

Neuroreflexotherapy

Not recommended in the U.S. until specifically trained and experienced clinicians are available.

Neurometer®

See Current perception threshold (CPT) testing.

Neuromodulation devices

See Spinal cord stimulators.

Neuromuscular electrical stimulation (NMES devices)

Not recommended. NMES is used primarily as part of a rehabilitation program following stroke and there is no evidence to support its use in chronic pain. There are no intervention trials suggesting benefit from NMES for chronic pain. (Moore, 1997) (Gaines, 2004) The scientific evidence related to electromyography (EMG)-triggered electrical stimulation therapy continues to evolve, and this therapy appears to be useful in a supervised physical therapy setting to rehabilitate atrophied upper extremity muscles following stroke and as part of a comprehensive PT program. Neuromuscular Electrical Stimulation Devices (NMES), NMES, through multiple channels, attempts to stimulate motor nerves and alternately causes contraction and relaxation of muscles, unlike a TENS device which is intended to alter the perception of pain. NMES devices are used to prevent or retard disuse atrophy, relax muscle spasm, increase blood circulation, maintain or increase range-of-motion, and re-educate muscles. Functional neuromuscular stimulation (also called electrical neuromuscular stimulation and EMG-triggered neuromuscular stimulation) attempts to replace stimuli from destroyed nerve pathways with computer-controlled sequential electrical stimulation of muscles to enable spinal-cord-injured or stroke patients to function independently, or at least maintain healthy muscle tone and strength. Also used to stimulate quadriceps muscles following major knee surgeries to maintain and enhance strength during rehabilitation. (BlueCross BlueShield, 2005) (Aetna, 2005)

Neurontin® (gabapentin)

Neurontin® is a brand name for gabapentin produced by Pfizer subsidiary Parke-Davis. See Gabapentin.

NeuroPhysiologic Pain Profile (NP3)

Not recommended. There are no published studies. A private company NeuroPAS developed the NeuroPhysiological Pain Profile, or the NP3, and is trying to market it. For other tests, see Psychological evaluations; Cytokine DNA testing; Functional imaging of brain responses to pain; CRPS, diagnostic tests; Quantitative sensory threshold (QST) testing; Current perception threshold (CPT) testing; Genetic testing for potential opioid abuse.

Nexium® (esomeprazole magnesium)

See Proton pump inhibitors (PPIs), where it says, a trial of omeprazole or lansoprazole is recommended before Nexium therapy.

Nonprescription medications

The following are recommended:Acetaminophen (safest); NSAIDs (aspirin, ibuprofen). (Bigos, 1999) A 2008 Cochrane review found that NSAIDs are not more effective than acetaminophen for acute low-back pain, but acetaminophen had fewer side effects, which support recommending NSAIDs as a treatment option after acetaminophen. (Roelofs-Cochrane, 2008) There should be caution about daily doses of acetaminophen and liver disease if over 3 g/day or in combination with other NSAIDs. (Watkins, 2006) See also NSAIDs (non-steroidal anti-inflammatory drugs).

Norepinephrine serotonin reuptake inhibitors (NSRIs)

See Duloxetine (Cymbalta®); & Milnacipran (Ixel®)

NSAIDs (non-steroidal anti-inflammatory drugs)

Specific recommendations:

Osteoarthritis (including knee and hip): Recommended at the lowest dose for the shortest period in patients with moderate to severe pain. Acetaminophen may be considered for initial therapy for patients with mild to moderate pain, and in particular, for those with gastrointestinal, cardiovascular or renovascular risk factors. NSAIDs appear to be superior to acetaminophen, particularly for patients with moderate to severe pain. There is no evidence to recommend one drug in this class over another based on efficacy. In particular, there appears to be no difference between traditional NSAIDs and COX-2 NSAIDs in terms of pain relief. The main concern of selection is based on adverse effects. COX-2 NSAIDs have fewer GI side effects at the risk of increased cardiovascular side effects, although the FDA has concluded that long-term clinical trials are best interpreted to suggest that cardiovascular risk occurs with all NSAIDs and is a class effect (with naproxyn being the safest drug). There is no evidence of long-term effectiveness for pain or function. (Chen, 2008) (Laine, 2008)

See DWC MTUS chapter on Low Back Complaints.



Neuropathic pain: There is inconsistent evidence for the use of these medications to treat long-term neuropathic pain, but they may be useful to treat breakthrough pain and mixed pain conditions such as osteoarthritis (and other nociceptive pain) in patients with neuropathic pain. (Namaka, 2004) (Gore, 2007)

See NSAIDs, GI symptoms & cardiovascular risk; NSAIDs, hypertension and renal function; & Medications for acute pain (analgesics). Besides the above well-documented side effects of NSAIDs, there are other less well-known effects of NSAIDs, and the use of NSAIDs has been shown to possibly delay and hamper healing in all the soft tissues, including muscles, ligaments, tendons, and cartilage. (Maroon, 2006) The risks of NSAIDs in older patients, risks which include increased cardiovascular risk and gastrointestinal toxicity, may outweigh the benefits of these medications. (AGS, 2009)



NSAIDs, GI symptoms & cardiovascular risk

Recommend with precautions as indicated below.

Clinicians should weight the indications for NSAIDs against both GI and cardiovascular risk factors.

Determine if the patient is at risk for gastrointestinal events: (1) age > 65 years; (2) history of peptic ulcer, GI bleeding or perforation; (3) concurrent use of ASA, corticosteroids, and/or an anticoagulant; or (4) high dose/multiple NSAID (e.g., NSAID + low-dose ASA). A history of ulcer complications is the most important predictor of future ulcer complications associated with NSAID use. (Garcia Rodriguez, 1994) (Malfertheiner, 2009)

H. Pylori and NSAID use: While routine screening for H. Pylori is not indicated in patients who are about to start NSAIDs, eradication of H pylori prior to initiation of therapy has been suggested to reduce subsequent risk of GI ulceration. At best, consensus guidelines indicate pre-screening for H. Pylori prior to starting NSAID treatment for those with GI risk factors for ulceration as listed above. Eradication of H. pylori alone is not sufficient to prevent ulcer bleeding in NSAID users with high gastrointestinal risk. There are no clear-cut guidelines for treatment of H. Pylori after initiation of NSAID treatment and this topic remains controversial. At this time, there is currently no evidence to support the routine use of a proton-pump inhibitor in a patient without the above GI risk factors for ulceration who has had a history of eradicated H. Pylori (i.e. a previous history of treated H. Pylori without evidence of ulceration is not an indicator for either the use of a Cox-2 NSAID or a proton-pump inhibitor). Consensus guidelines do currently indicate that patients who have a history of GI ulceration (which was determined to be secondary to H. Pylori) who develop breakthrough dyspepsia while treated with a proton-pump inhibitor should have the following: (1) NSAID therapy withheld; & (2) GI evaluation undertaken. (Malfertheiner, 2009) (Chan, 2001) (Fock, 2009) (Laine, 2006) (Chan, 2002) (Garcia Rodriguez, 1994)

Recommendations

Patients with no risk factor and no cardiovascular disease: Non-selective NSAIDs OK (e.g., ibuprofen, naproxen, etc.)

Patients at intermediate risk for gastrointestinal events and no cardiovascular disease: (1) A non-selective NSAID with either a PPI (Proton Pump Inhibitor, for example, 20 mg omeprazole daily) or misoprostol (200 µg four times daily) or (2) a Cox-2 selective agent. Long-term PPI use (> 1 year) has been shown to increase the risk of hip fracture (adjusted odds ratio 1.44).

Patients at high risk for gastrointestinal events with no cardiovascular disease: A Cox-2 selective agent plus a PPI if absolutely necessary.

Patients at high risk of gastrointestinal events with cardiovascular disease: If GI risk is high the suggestion is for a low-dose Cox-2 plus low dose Aspirin (for cardioprotection) and a PPI. If cardiovascular risk is greater than GI risk the suggestion is naproxyn plus low-dose aspirin plus a PPI. (Laine, 2006) (Scholmerich, 2006) (Nielsen, 2006) (Chan, 2004) (Gold, 2007) (Laine, 2007)

Cardiovascular disease: A non-pharmacological choice should be the first option in patients with major cardiac risk factors. It is then suggested that acetaminophen or aspirin be used for short-term needs.

Major risk factors (recent MI, or coronary artery surgery, including recent stent placement): If NSAID therapy is necessary, the suggested treatment is naproxyn plus low-dose aspirin plus a PPI.

Mild to moderate risk factors: If long-term or high-dose therapy is required, full-dose naproxen (500 mg twice a day) appears to be the preferred choice of NSAID. If naproxyn is ineffective, the suggested treatment is (1) the addition of aspirin to naproxyn plus a PPI, or (2) a low-dose Cox-2 plus ASA. Cardiovascular risk does appear to extend to all non-aspirin NSAIDs, with the highest risk found for the Cox-2 agents. (Johnsen, 2005) (Lanas, 2006) (Antman, 2007) (Laine, 2007)

Use with Aspirin for cardioprotective effect:

In terms of GI protective effect: The GI protective effect of Cox-2 agents is diminished in patients taking low-dose aspirin and a PPI may be required for those patients with GI risk factors. (Laine, 2007)

In terms of the actual cardioprotective effect of aspirin: Traditional NSAIDs (both ibuprofen and naproxen) appear to attenuate the antiplatelet effect of enteric-coated aspirin and should be taken 30 minutes after ASA or 8 hours before. (Antman, 2007) Cox-2 NSAIDs and diclofenac (a traditional NSAID) do not decrease anti-platelet effect. (Laine, 2007)

Use of NSAIDs and SSRIs: The concurrent use of SSRIs and NSAIDs is associated with moderate excess relative risk of serious upper GI events when compared to NSAIDs alone. This risk was higher for non-selective NSAIDs when compared to Cox-2 selective agents (adjusted odds ratio of 1.77 and 1.33, respectively). (Helin-Salmivaara, 2007) In particular, it is suggested that in individuals at increased risk for GI bleeding (see above) a consideration be made to switch to an antidepressant with a lower degree of inhibition of serotonin reuptake (Intermediate reuptake: venlafaxine, amitriptyline, imipramine, citalopram; Low reuptake: desipramine, doxepin, trazodone, bupropion, mirtazapine). SSRIs with the highest degree of inhibition of serotonin reuptake include paroxetine, sertraline, and fluoxetine. (Looper, 2007)

Treatment of dyspepsia secondary to NSAID therapy: Stop the NSAID, switch to a different NSAID, or consider H2-receptor antagonists or a PPI.

A recent systematic review concluded that slow-release formulations of NSAIDs are associated with a greater risk of upper GI bleeding/perforation, and should be used with care. The RR of upper GI bleeding/perforation was 4.50 for traditional NSAIDs, 2.69 for ibuprofen, and 1.88 for coxibs. Estimated RRs were 5.63 for naproxen immediate release, but as much as 14.54 for some slow-release formulations. (Massó, 2010) In patients with prior myocardial infarction (MI), most NSAIDs are associated with an increased risk for death and recurrent MI, a large cohort study concludes. Use of NSAIDs was associated with a 45% increased risk for death or recurrent MI in the first 7 days of treatment and a 55% increased risk if treatment continued to 3 months. There is no apparent safe therapeutic window for NSAIDs in patients with prior MI and low-dose and short-term use of NSAIDs are not safe. All NSAIDs except naproxen were associated with an increased risk for death or recurrent MI, with diclofenac having the highest risk (RR in the first week of treatment, 3.26), an even higher cardiovascular risk than the selective COX-2 inhibitor rofecoxib, which was withdrawn from the market due to its unfavorable cardiovascular risk profile. (Schjerning, 2011) A large systematic review of available evidence on NSAIDs confirms that naproxen and low-dose ibuprofen are least likely to increase cardiovascular risk. Rofecoxib (Vioxx) was associated with a significantly increased risk of cardiovascular events and was taken off the market, but diclofenac, a widely used NSAID, also poses an equivalent risk to patients. Indomethacin is an older, rather toxic drug, and the evidence on cardiovascular risk casts doubt on its continued clinical use. Naproxen was consistently shown to be safe, even at high doses, suggesting it should be the NSAID of choice in patients with increased cardiovascular risk. Naproxen was shown to be safer than ibuprofen, with the risk of cardiovascular events increasing with ibuprofen at daily doses ranging from 1200 mg to 1600 mg. If ibuprofen is used in high-risk patients, the dose should be kept low, but if a higher dose is needed, clinicians should switch to naproxen. Celecoxib (Celebrex), on the whole, had an increased risk of cardiovascular events at low and high doses, and should not be used in patients at high risk of cardiovascular disease. The authors commented that 10 years ago there were many NSAIDs in widespread use, but the number of drugs considered safe to use has declined substantially, down to just two, naproxen and low-dose ibuprofen. (McGettigan, 2011) There is a high prevalence of current NSAID use among groups at-risk for significant drug-related adverse events or who have major chronic conditions that are relative contraindications to NSAID use. (Adams, 2011) A new meta-analysis looking at the vascular and gastrointestinal effects of NSAIDs shows that the vascular risks associated with high-dose diclofenac and possibly ibuprofen are similar to the established risks associated with coxibs. High-dose naproxen, however, was associated with less vascular risk than the other NSAIDs. Further analysis suggested that these risks can be predicted for individuals. The authors found that major vascular events were increased by about one third by a coxib or diclofenac, chiefly due to an increase in major coronary events. Compared with placebo, they note, of 1000 patients allocated to a coxib or diclofenac for a year, 3 more had major vascular events, 1 of which was fatal. NSAIDs increased the risk for upper gastrointestinal complications by 2 to 4 times, although coxibs yielded the lowest risk for these complications. Long-term use of high dose NSAIDs should be reserved for those who receive considerable symptomatic benefit from the treatment and understand the risks. (Bhala, 2013)

NSAIDs, hypertension and renal function

Recommend with precautions as indicated below.

NSAIDs can increase blood pressure by an average of 5 to 6 mm in patients with hypertension. They may cause fluid retention, edema, and rarely, congestive heart failure. (Sustained blood pressure elevation in the elderly is associated with increases in hemorrhagic stroke, congestive heart failure and ischemic cardiac events.) The risk appears to be higher in patients with congestive heart failure, kidney disease or liver disease.



Normotensive patients: NSAIDs appear to have minimal effect on blood pressure in normotensive patients. (Laine, 2007)

Hypertensive patients: All NSAIDs have the potential to raise blood pressure in susceptible patients. The greatest risk appears to occur in patients taking the following anti-hypertensive therapy: angiotensin-converting enzyme (ACE) inhibitors; angiotensin receptor blockers; beta-blockers; or diuretics. In addition congestive heart failure may develop due to fluid retention.

Patients with mild to moderate renal dysfunction: All NSAIDs are relatively contraindicated in patients with renal insufficiency, congestive heart failure, or volume excess (such as cirrhosis). Oral opioids are an option for treatment.

Treatment recommendations: Blood pressure should be measured as well as evidence of fluid excess in normotensive patients within 2-4 weeks of beginning treatment and on each visit.

NSAIDs, specific drug list & adverse effects

Recommended with cautions below. Disease-State Warnings for all NSAIDs: All NSAIDS have [U.S. Boxed Warning]: for associated risk of adverse cardiovascular events, including, MI, stroke, and new onset or worsening of pre-existing hypertension. NSAIDS should never be used right before or after a heart surgery (CABG - coronary artery bypass graft). NSAIDs can cause ulcers and bleeding in the stomach and intestines at any time during treatment (FDA Medication Guide). See NSAIDs, GI Symptoms and Cardiovascular Risks. Other disease-related concerns (non-boxed warnings): Hepatic: Use with caution in patients with moderate hepatic impairment and not recommended for patients with severe hepatic impairment. Borderline elevations of one or more liver enzymes may occur in up to 15% of patients taking NSAIDs. Renal: Use of NSAIDs may compromise renal function. FDA Medication Guide is provided by FDA mandate on all prescriptions dispensed for NSAIDS. Routine Suggested Monitoring: Package inserts for NSAIDs recommend periodic lab monitoring of a CBC and chemistry profile (including liver and renal function tests). There has been a recommendation to measure liver transaminases within 4 to 8 weeks after starting therapy, but the interval of repeating lab tests after this treatment duration has not been established. Routine blood pressure monitoring is recommended. Overall Dosing Recommendation: It is generally recommended that the lowest effective dose be used for all NSAIDs for the shortest duration of time consistent with the individual patient treatment goals. Specific NSAID Classes are outlined below:

Selective COX-2 NSAIDS: Celecoxib (Celebrex®) is the only available COX-2 in the United States. No generic is available. Mechanism of Action: Inhibits prostaglandin synthesis by decreasing cyclooxygenase-2 (COX-2). At therapeutic concentrations, cyclooxygenase-1 (COX-1) is not inhibited. In animal models it works as an anti-inflammatory, analgesic, and antipyretic. It does not have an anti-platelet effect and is not a substitute for aspirin for cardiac prophylaxis. Use: Relief of the signs and symptoms of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, and treatment of acute moderate pain. Side Effects: See NSAIDs, hypertension and renal function; & NSAIDs, GI Symptoms and Cardiovascular Risks. Cardiovascular: Hypertension (≤13%) CNS: headache (15.8%), dizziness (1% - 2%), insomnia (2.3%); GI: diarrhea (4% to 11%), dyspepsia (8.8% vs. 12.8% for ibuprofen and 6.2% for placebo), diarrhea (5.6%), abdominal pain (4.1% vs. 9% for ibuprofen and 2.8% for placebo), N/V (3.5%), gastroesophogeal reflux (≤ 5%), flatulence (2.2%); Neuromuscular/ skeletal: arthralgia (7%), back pain (3%); Respiratory: upper respiratory tract infection (8%), cough (7%), sinusitis (5%), rhinitis (2%), pharyngitis (2%); Skin Rash (2%) – discontinue if rash develops; Peripheral Edema (2.1%). Recommended Dose: 200 mg a day (single dose or 100 mg twice a day). (Celebrex® package insert)



Combination (NSAID/GI protectant): Arthrotec® (diclofenac/ misoprostol) 50mg/200mcg, 75mg/20mcg. [Black Box Warning]: Do not administer Arthrotec®/misoprostol to pregnant women because it can cause abortion. Mechanism of action: Combines a diclofenac (an NSAID) with misoprostol, an agent that inhibits basal and nocturnal gastric acid secretion and has some mucosal protective properties. Misoprostol is available as Cytotec®. Uses: Indicated for the treatment of the signs and symptoms of osteoarthritis in patients at high risk for developing NSAID-induced gastric or duodenal ulcers and their complications. These two products are available as separate medications if you need to individualize therapy. Side Effects: See diclofenac. Misoprostol side effects: (vs. diclofenac alone). The following symptoms were increased over and above that found for diclofenac alone with the addition of misoprostol: Abdominal pain (21% with Arthrotec and 15% with diclofenac); Diarrhea (19% with Arthrotec vs. 11% with diclofenac); Dyspepsia (14% for Arthrotec vs. 11% for diclofenac); Nausea/vomiting (11% for Arthrotec vs. 6% for diclofenac); Flatulence (9% for Arthrotec vs. 4% for diclofenac). Diarrhea and abdominal pain usually resolve in 2 to 7 days. Dosing: The recommended dose for OA is diclofenac 50mg/misoprostol 200mcg t.i.d. In patients that may not tolerate this dose, 50mg/200mcg b.i.d and 75mg/200mcg b.i.d. may be prescribed, but are somewhat less effective in ulcer prevention. (Arthrotec® Package Insert) (Bocanegra, 1998)
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