PAIN

PAIN

  1. 1
    Current Diagnosis

    • Always use history and physical examination and consider imaging or laboratory studies to rule out life- or function-threatening pathologies before merely providing symptomatic treatment.

    Acute Pain

    • Acute pain has a sudden onset, is usually nociceptive (somatic, visceral) in nature, and likely is due to apparent injury or medical condition.

    • It can last up to 3 months and can demonstrate hypersympathetic signs of tachycardia, elevated blood pressure, dilated pupils, or diaphoresis.

    Chronic Pain

    • Chronic pain is usually gradual in onset, lasts more than 3 months, and rarely serves any purpose. It can manifest with hyperalgesia (hurts more than it should) or allodynia (hurts when it should not, e.g., light touch).

    • Vegetative symptoms such as depression, fatigue, or anorexia may be present.

    •   A significant neuropathic component may be present.

    • Psychiatric and social or socioeconomic issues may be exacerbating factors.

    • Examples can include headaches, low back pain, osteoarthritis, and fibromyalgia.

    Quality

    • Quality of the pain (e.g., sharp, dull, radiating, deep, superficial, lancinating, tingling, burning) is an important factor in determining the best management modalities.

    • Quality plays a role in ruling in or ruling out severe disease that can require urgent surgical or other interventions rather than analgesics or adjunctive medications or therapies.

    Severity

    • Severity of the pain can be rated on a variety of scales such as numerical (0–5, 0–10), analogue (marked on a line with a range from no pain to the worst possible pain), or facial expression (smiles to grimaces, available for children and the elderly or patients with dementia).

    • Functional scales (fully satisfactory function to debilitated) may be more helpful in determining the impact of the pain on the person’s life.

  2. 2
    Current Therapy

    Acute pain commonly responds to simple analgesics of the nonopioid, opioid, or combination varieties. Rest, ice, compression, and elevation (RICE) are helpful for acute inflammatory conditions and injuries.

    Adjuvant medications are drugs that are used for pain but do not have pain treatment as their primary indication.

    •   Chronic pain, because of its complexity, often requires multiple modalities. Pharmacologic options include nonopioid, opioid, adjuvant, or homeopathic medications. Nonpharmacologic options include physical therapy, chiropractic care, transcutaneous electrical nerve stimulation (TENS) unit, acupuncture, or surgical or anesthesia interventions.

    •   Opioids are sometimes safer for long-term use, but the individual’s risk for falls must be considered in the elderly, as opioids can increase this risk, and the risk of overdose rises with increasing age. For many chronic conditions such as low back pain, the evidence supporting the use of opioids is lacking, with efficacy often superseded by nonopioid medications. The risk of addiction MUST be considered before starting opioids on any patient. Since 1999, opioid overdose deaths as a proportion of all deaths has increased by 265% in men and 400% in women.

    •   NSAIDs carry a risk for GI and cardiac complications, especially in the elderly and those with a history of CAD or GI ulcers or gastritis.

    •   Adjuvant medications are often the most effective agents in neuropathic pain.

    •   The patient must be involved in and cooperative with the treatment plan. Honesty and trust are necessary components of a therapeutic physician–patient relationship.

    •   Do not underestimate the placebo effect. If the patient feels that a harmless treatment is beneficial, take advantage of it.

    •   If the patient is not improving adequately, consult a surgeon if the source of pain is an operable condition, or consult a pain specialist if surgical intervention is not appropriate.

  3. 3
    Epidemiology

    Approximately 50 million Americans experience chronic pain, with annual expenditures and overall economic impact estimated at $85 to $90 billion. Pain is the most common symptom that causes patients to pursue medical evaluation and management. The prevalence of several common pain syndromes including headaches, facial pain, abdominal pain, pelvic pain, and low back pain is slightly higher in women than in men because there are gender variations in the perception, coping, and reporting of pain. Pain tends to be undertreated in women, people of color, children, and the elderly, and it is underreported in nonverbal or cognitively impaired children and adults.

  4. 4
    Risk Factors

    Traumatic injury is a cause of acute pain and a risk factor for chronic pain. Patients who have mastectomy, laminectomy, thoracotomy, or amputations are at risk for pain syndromes. Chronic musculoskeletal conditions such as arthritis, spinal stenosis, degenerative disk disease, or fibromyalgia; infectious diseases including HIV or varicella zoster; neuropathies from diagnoses such as diabetes, B12 deficiency, or multiple sclerosis; treatment with certain chemotherapies or isoniazid (INH) without adequate vitamin B6; psychiatric disorders such as depression, anxiety, or posttraumatic stress disorder (PTSD), especially as a consequence of domestic violence; or autoimmune disorders including lupus and rheumatoid arthritis can predispose the individual to chronic pain. Although the risk of pain increases with age, pain should not be considered a usual part of aging until it is appropriately evaluated. A motor vehicle accident or work-related injury or other condition where secondary gain is a possibility, especially if there is no apparent injury, raises the consideration of malingering.

  5. 5
    Pathophysiology

    Injury or potential injury is detected by nociceptors in the peripheral nervous system, and the signal is then transmitted through the dorsal horn of the spinal cord up to the brain for processing. The three primary classes of opioid receptors are the mu, kappa, and delta receptors, and they are located in areas throughout the central and peripheral nervous system. Upon binding these receptors, opioids block calcium channels and modulate the nociceptive pathways. The hyperstimulation of chronic pain and the resultant increase in intracelluar calcium are neurotoxic due to lowering neuronal firing threshold and increasing firing frequency. This neurotoxicity can lead to ongoing pain in the absence of physical insult. Neuropathic pain can result from chronic pain or from physical or pathophysiologic injury or changes to the nerve, as in diabetic neuropathy or other neuropathies.

  6. 6
    Prevention

    The best prevention is a safe and healthy lifestyle. The combination of healthy diet and exercise has been demonstrated to improve pain in osteoarthritis better than either intervention alone, and maintaining a healthy weight can help to prevent the arthritis in the first place.

    Smoking and obesity have been associated with chronic pain. Regarding safety, wearing seat belts while driving or using appropriate safety equipment at work and during recreational activities can help to reduce the severity of injuries should they occur. Proper body mechanics are important as well.

  7. 7
    Clinical Manifestations

    Manifestations of pain depend upon the location and underlying cause. In the acute setting, the patient can have tachycardia, elevated blood pressure, or diaphoresis, whereas chronic pain can manifest with vegetative symptoms of depression, fatigue, anorexia, or insomnia.

  8. 8
    Diagnosis

    Pain is most commonly a symptom rather than a disease in and of itself, so it behooves the provider to pursue treatable causes, especially red flag conditions, in addition to providing symptomatic treatment. The history regarding onset (shorter or longer than 3 months), exacerbating or remitting factors, quality, radiation, severity, and timing of the pain (constant vs. intermittent), in addition to any associated signs or symptoms such as fever, nausea, vomiting, or diarrhea, can help the provider in that regard. The physical examination is a key component in ruling out life- or function- threatening disorders. Is there tenderness, swelling, bruising, erythema, or deformity? Are strength, reflexes, and sensation intact?

    Does the patient demonstrate a consistent demeanor (grimace or other signs of pain) and gait (antalgic vs. normal) when moving from the waiting area to the examination room and out to the parking lot? The choice to use laboratory studies or imaging is determined by the location of the pain and the structures or organs that might be in that area. When determining severity, “What does the pain keep you from doing?” (which uses function as the measure of impairment and treatment efficacy rather than a subjective pain score to guide therapy) may be a much more helpful question than “How bad is your pain?”

    If function is not improving, that could be considered a treatment failure, and medications and therapy should be adjusted rather than continuing the same regimen.

  9. 9
    Differential Diagnosis

    The differential diagnosis for all types of pain is far too extensive for the brevity of this chapter, but in addition to the plethora of physical diagnoses to be considered, the provider has to consider that chronic fatigue, depression, and domestic abuse can manifest as a chronic pain syndrome.

  10. 10
    Treatment

    Nonpharmacologic

    Physical therapy (for chronic pain. For recent-onset low back pain, relief was statistically but not clinically significant as compared to usual care.), TENS units, chiropractic care, and regular exercise have shown benefit in certain conditions. Cognitive behavioral therapy and mindfulness training improve function more than pain. Surgery may be required, and interventions such as vertebroplasty, nerve blocks, and epidural injections may also be of benefit. Aerobic exercise and water therapy are helpful for fibromyalgia, but the patient must not overexert because this can exacerbate the pain.

    Pharmacologic

    Nonopioid Analgesics

    Acetaminophen (Tylenol) is generally a safe and effective medication as long as the total daily dose for adults remains less than 3 g/day. For osteoarthritis of the hips and knees, paracetamol provides only modest short-term benefit, and it is not effective for the management of low back pain. However, due to its relative safety as compared to other medications, it is certainly worth a try. Chronic use can increase the likelihood of transaminase elevations four-fold, so this is a consideration when patients are using other potentially hepatotoxic medications.

    Numerous NSAIDs are available, but none has been shown to be superior to another except for the convenience of dosing daily versus every 6 hours. All are generally safe in the acute setting but should be used with caution if needed long term, and they should be avoided altogether for long-term use in the elderly or patients with cardiovascular, renal, or peptic ulcer disease. This caution includes the cyclooxygenase (COX)-2–specific drugs. Naproxen seems to have the best cardiac profile while the COX-2 drugs tend to have the best GI profile. Misoprostol or proton pump inhibitors can be used for GI prophylaxis.

    Topical agents such as diclofenac (Flector 1.3% Patch, Voltaren 1% Gel), menthol, camphor, lidocaine, and capsaicin (Zostrix, Qutenza) are effective in some patients.

    Opioids (see Table 1)

    For patients with inadequate response to the non-opioid analgesics, opioids are an option (Table 1). However, the proven efficacy for cancer pain and palliative care as well as some acute pain conditions cannot be extrapolated to chronic pain syndromes. The benefits of opioids in some conditions and the overall safety of opioids have been called into question due to the dramatic increase in opioid abuse and opioid overdose deaths. Recent research has demonstrated a twofold to threefold increase in all-cause mortality with chronic opioid use, especially if using more than 200 mg/day morphine equivalent and/or sustained-release or long-acting (methadone) preparations.

    Additionally, risk of overdose death is increased to 3.7 to 4.6-fold at doses of 50–100 mg/day MED as compared to MED of less than 20 mg/day. According to the CDC, opioids were implicated in 71% of the pharmaceutical overdose deaths in 2013, and 60% were legally prescribed by a single provider. Opioids might be a safer option in the elderly as compared to NSAIDs, but they can increase fall risk. They should be avoided in patients with untreated sleep apnea because of increased risk for complications, especially in combination with benzodiazepines. This risk increases with age with as much as an 8- fold increase for those older than 80 years of age. The risk of postoperative respiratory depression also increases with age. The risks of using chronic opioids likely outweigh the benefits in the management of headache, fibromyalgia and chronic low back pain according to a 2014 position paper from the American Academy of Neurology.

    Table 1

    Opioid Analgesics

    Abbreviations: APAP = acetaminophen (N-acetyl-p-aminophenol); CNS = central nervous system; CrCl = creatinine clearance; MED = morphine equivalent dose; MAOI = monoamine oxidase inhibitor; NMDA = N-methyl-d-aspartate; TIRF-REMS = Transmucosal Immediate- Release Fentanyl Risk-Evaluation and Mitigation  Strategy.

    *  Only approved in the United States for the treatment of opioid  dependence.

    †  Sustained-release formulations should never be  crushed.

    The risks and the adverse outcomes (abuse, addiction, overdose, death) related to this class of medications culminated in the release of guidelines with twelve recommendations from the CDC in March 2016 for the prescribing of opioids for chronic pain. A brief summary of the author’s recommendations: 1) Nonpharmacologic therapy and nonopioids are preferred for chronic pain. 2) Benefits of opioids on pain and function need to outweigh the risks. Screen for risk of dependence. 3) Establish treatment goals with the patient and discuss plan to discontinue opioids if treatment fails. 4) On initiation, use immediate release rather than ER/LA (extended release, long-acting) preparations. 5) Use the lowest effective dose, and reassess risks if dose is increased, especially if greater than 50 mg MED (morphine equivalent dose) per day. [See Table 1 for equivalent doses.]. 6) Acute pain should be treated acutely; less than three days usually but no more than seven days. 7) Reassess within one to four weeks of initiation of treatment or dose escalation and at least every three months thereafter. Discontinue if benefits do not justify risk. 8) Consider prescribing naloxone if there is concurrent benzodiazepine use, a history of overdose, or MED > 50 mg/day. 9) Use state drug monitoring programs at initiation and at least every three months. 10) Obtain a urine drug screen at initiation and at least annually. The prescribed medications and nothing else should be present. [Additionally, consider testing periodically for the presence of prescribed NSAIDs and adjuvant medications to assess compliance with the whole treatment plan rather than just the opioid.]. 11) Avoid concurrent with benzodiazepines. 12) Offer or arrange evidence-based treatment for patients with opioid use disorder.

    Tramadol (Ultram) is a weak mu agonist and an inhibitor of norepinephrine and serotonin uptake, a quality that gives it a niche in the treatment of neuropathic and radicular pain.1 It is the only opioid studied for fibromyalgia1 in a randomized trial. A recent study has demonstrated an increased risk for hypoglycemia, notably in the first 30 days of treatment with tramadol.

    Codeine is a prodrug that has to be converted to morphine to be effective, and about 10% of the population lacks the cytochrome P450 2D6 enzyme that makes the conversion, resulting in poor analgesic response. Owing to the need for conversion, doses exceeding 60 mg do not increase benefit because the enzyme system is saturated. Use caution when prescribing codeine to children as deaths have been reported, even with the use of age- and weight-appropriate dosages, as a result of the hypermetabolism of codeine to morphine.

    Morphine is the prototype for the opioids. It is extremely versatile, it can be given via almost any route, and it is available in multiple dosages and preparations ranging from liquid to daily sustained release. Hydromorphone (Dilaudid, Exalgo) shares similar qualities but is more potent. Hydrocodone is only available in a sustained- release oral form (Zohydro ER, Hysingla ER), and in combination with acetaminophen (Lortab, Norco). It was rescheduled by the DEA to schedule II in 2014. It had been the number one prescribed medication in the US for several years until the rescheduling which led to >20% reduction in prescriptions and >16% reduction in tablets dispensed.

    Methadone (Dolophine) is the longest acting of the opioids at a half- life of 23 hours, although the duration of action can be variable. It is active as an N-methyl-d-aspartate (NMDA) receptor antagonist, inhibits norepinephrine and serotonin uptake, and is an agonist at the mu receptor. Therefore, methadone can be effective when other opioids fail, especially in the case of chronic or neuropathic pain,1 where the NMDA-receptor is more of a factor in pain control. It must be used with caution (Table 2) because it can prolong the QT interval and has an increased dose-dependent risk of respiratory depression as compared to other opioids.

    Table 2

    Morphine and Methadone Equivalents

     

    Morphine (Daily Requirement) Methadone Equivalent
    < 500 mg 5:1
    500–1000 mg 10:1
    > 1000 mg 20:1

    Acute pain: methadone = morphine (1:1). Chronic pain: The above conversion is for illustration of the complexity of methadone use. A more-detailed table should be referenced before prescribing, and methadone should be used with extreme caution because of the risk for cardiac complications and respiratory  depression.

    Meperidine (Demerol) is relatively weak compared to morphine and others, and it is limited by poor oral bioavailability, a 48-hour acute pain indication, and the neurotoxicity of one of its metabolites, normeperidine (renally cleared, so it is contraindicated in renal patients). Other opioids are safer and more effective, so its use should be limited.

    The mu agonists do not technically have a ceiling dose; however, the dose should be limited to the lowest effective dose. In the purely palliative or hospice patient, the dosage may be titrated to effect until the pain is relieved or side effects limit the dosage.

    The mixed agonist-antagonists such as nalbuphine (Nubain), pentazocine (Talwin), and butorphanol (Stadol) tend to have a higher incidence of hallucination and confusion, and, because they are agonists at kappa and delta receptors and antagonists at the mu receptor, they can produce withdrawal symptoms in patients who are routinely taking mu agonists. The partial agonist buprenorphine (Butrans patch, Subutex,1 Buprenex) is dose limited because it has a maximal effective dose as well as a potential to cause QT prolongation.

    Patients who are taking opioids on a chronic basis should use a stimulant laxative such as senna with or without docusate because fiber and dietary modification are usually inadequate for opioid- induced constipation, and fiber can aggravate the problem.

    Lubiprostone (Amitiza) can be used for opioid-induced constipation at the 24 mcg twice a day dose. Naloxegol (Movantik) and methylnaltrexone (Relistor) are peripheral rather than central mu- antagonists, so they are indicated for managing opioid-induced constipation without negatively impacted pain control. Bisacodyl should not be used chronically due to its potential to damage the myenteric plexus of the gut and cause severe and permanent impairment of colonic motility.

    As a word of caution, recent research has demonstrated a twofold to threefold increase in all-cause mortality with chronic opioid use, especially if using more than 200 mg/day morphine equivalent and/or sustained-release or long-acting (methadone) preparations.

    Additionally, risk of overdose death is increased to 3.7 to 4.6-fold at doses of 50-100 mg/day MED as compared to MED of less than 20 mg/day. The risk of postoperative respiratory depression increases with age. The risks of using chronic opioids likely outweigh the benefits in the management of headache, fibromyalgia and chronic low back pain according to a 2014 position paper from the American Academy of Neurology.

    Adjuvant Drugs

    Adjuvant medications are drugs that are useful in the management of pain but do not have pain treatment as an indication. Some adjuvant medications such as duloxetine (Cymbalta) and pregabalin (Lyrica) have received an FDA indication for diabetic peripheral neuropathic pain. Tricyclic antidepressants are useful for chronic pain and they have the benefit, unlike duloxetine, of working at the lowest doses rather than having to titrate to the maximum dose to gain benefit.

    Several anticonvulsants have demonstrated efficacy in the management of pain, most notably gabapentin (Neurontin),1 pregabalin (Lyrica), and carbamazepine (Tegretol).1 Others have been tested in trials, but these three have the most evidence to support their use. Gabapentin and pregabalin have the benefit of not requiring monitoring of blood levels or for marrow, liver, or renal toxicities.

    Gabapentin (Neurontin) has been beneficial using a single dose of 1200 mg preoperatively, notably in combination with celecoxib, in reducing postoperative opioid requirements in mastectomy, laminectomy, and thoracotomy patients.

    Corticosteroids can be beneficial in inflammatory conditions, nerve or spinal cord compression, or increased intracranial pressure due to neoplasms. Any can help, but blood pressure elevations and fluid retention can be problematic in all but dexamethasone (Decadron),1 which lacks mineralocorticoid activity. Steroids also have the downside of elevating blood glucose and, in long-term use, causing osteoporosis.

    Muscle relaxants may be beneficial if muscle spasm is a source of pain, but there is insufficient evidence to determine relative efficacy or safety. Of these, two stand out: metaxalone (Skelaxin), which lacks the black-box warning for the operation of heavy equipment, and tizanidine (Zanaflex), which can antagonize α1 receptors in the spinal cord to provide additional pain relief. In chronic use, the patient will need to be monitored for anemia and leukopenia with metaxalone and for liver abnormalities with tizanidine. Cyclobenzaprine plus naproxen was not superior to naproxen alone for low back pain.

    Calcitonin (Miacalcin)1 has shown very modest benefit for pain due to osteoporotic vertebral compression fractures, but it shows no benefit for compression fractures due to bone metastasis.

    Ziconotide (Prialt) has demonstrated benefit as well as safety for long-term pain management, but it is limited to only intrathecal use owing to gastrointestinal side effects.

    Caffeine can modulate pain via action upon adenosine receptors that are involved in nociceptions. It is found in several over-the- counter analgesics, notably for migraine treatment. Regarding alternative medications, riboflavin,1,7 butterbur,1,7 and coenzyme Q10

    (CoQ10)1,7 are effective for migraine prophylaxis. Glucosamine sulfate7 (not HCl), S-adenosylmethionine (SAM-e),1,7 methylsulfonylmethane (MSM),1,7 and willow bark1,7 are likely effective for arthritic and low- back pain.

    Acetyl-L-carnitine (ALC) had demonstrated efficacy in diabetic neuropathy at 2–3 gm/day. Capsaicin 0.075% cream and 8% patch have demonstrated benefit for peripheral neuropathy, post-herpetic neuralgia, and HIV-associated neuropathy.

    Numerous medications in multiple drug classes have been studied for fibromyalgia, but many of the trials are small and/or of poor quality. Of these drugs, duloxetine (Cymbalta), pregabalin (Lyrica) and milnacipran (Savella) have received an FDA indication for fibromyalgia; and gabapentin (Neurontin),1 ondansetron (Zofran),1 and naltrexone (Depade, ReVia)1 demonstrated modest benefit.

    The use of cannabinoids has become legal in some states; however, their use for the management of pain is somewhat controversial as the studies evaluating these drugs are often of low to modest quality. A 2015 systematic review and meta-analysis showed mild reductions in pain, but the comparison groups were placebo rather than standard care. Additionally, cannabinoids are not without adverse effects, including impacts on cognition, motivation, and psychosis in a 2016 review. Negative impacts could be even greater as unintended consequences of medical and/or recreational use come to light.

     

  11. 11
    Monitoring

    Controlled-substance agreements are beneficial in setting the boundaries for the use of opioid pain relievers (Figure 1). Routine visits are necessary to document ongoing need for and adequate response to the prescribed regimen. Routine drug screening is beneficial for monitoring compliance with the opioid as well as nonopioid medications. However, the provider needs to be aware of the metabolites of the different drugs. Hydromorphone (Dilaudid) and oxymorphone (Opana) are metabolites of hydrocodone (Lortab, Norco) and oxycodone (Percocet, Endocet, OxyContin), respectively.

    All states except Missouri have prescription-monitoring programs that allow providers to monitor for the use of multiple providers and pharmacies to obtain controlled medications. Rules governing the prescribing and use of controlled substances vary among states, so the provider should be knowledgeable of local regulations as well as Federal DEA requirements.

     

  12. 12
    Complications

    The Centers for Disease Control and Prevention (CDC) reported in 2011 that opioid pain relievers were involved in 73.8% of the 20,044 prescription drug overdose deaths, and this is believed to be an underestimate. Overdose death rates were three times greater in non- Hispanic whites and in American Indians and Alaska Natives than in blacks and Hispanic whites. The death rates were highest in the 35- to 54-years age range, producing a YPLL (years of potential life lost) comparable to that of motor vehicle accidents. Medicaid populations are at greater risk of opioid overdose than non-Medicaid populations, and prescription drug overdose death rates are higher in the more rural and impoverished counties.

    In addition to the deaths, there is a significant cost burden of substance abuse treatment admissions, with the 2008 rates being six times the 1999 rate. Nonmedical use of opioids represents up to $72.5 billion in health care costs. By 2010, opioids were sold in such a volume that every American adult could be treated for a month with hydrocodone 5 mg every 4 hours. Incidentally, 1999 is the year that several organizations began promoting “pain as the fifth vital sign,” with no secondary improvement in the quality of pain management. Drug addiction is very real, and about 15% of patients may be genetically predisposed to addiction; therefore, clinicians should strongly consider this in their risk/benefit analysis before exposing a patient to these powerful medications. Using a tool such as the Opioid Risk Tool may be helpful in determining the risk of addiction in a particular individual.

    Long-term safety of opioids has not been demonstrated, and chronic use has been associated with sleep disorders, adrenal suppression, and hypogonadism (and secondary erectile dysfunction and depression).

  13. 13
    References

    Baratloo A., Rouhipour A., Forouzanfar M.M., et al. The role of caffeine in pain management: A brief literature review. Anesth Pain Med. 2016;6(3):e33193 Published online March 26, 2016.

    Chou R., Peterson K., Helfand M. Comparative efficacy and safety of skeletal muscle relaxants for spasticity and musculoskeletal conditions. J Pain Sympt Manage. 2004;28:140– 175.

    Dowell D., Haegerich T.M., Chou R. CDC guideline for prescribing opioids for chronic pain — United States. JAMA. March 15, 2016.

    Fournier J.P., Azoulay L., Yin H., Montastruc J.L., Suissa S. Tramadol use and the risk of hospitalization in patients with noncancer pain. JAMA Intern Med. 2015;175(2):186–193.

    Franklin G.M. Opioids for Chronic Noncancer Pain: A Position Paper of the American Academy of Neurology. Neurology.

    2014;83:1277–1284.

    Fritz J.M., Magel J.S., McFadden M., Ashe C., Thackeray A., et al.

    Early physical therapy vs usual care in patients with recent- onset low back pain: A randomized clinical trial. JAMA.

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    D.N. Opioid dose and drug-related mortality in patients with nonmalignant pain. Arch Intern Med. 2011;171(6):686–691.

    Jellin J.M., Gregory P.J., et al. Pharmacist’s Letter/Prescriber’s Letter Natural Medicines Comprehensive Database. ed 12 Stockton, CA: Therapeutic Research Faculty; 2009.

    Jones C.M., Lurie P.G., Throckmorton D.C. Effect of US drug enforcement administration’s rescheduling of hydrocodone combination analgesic products on opioid analgesic prescribing. JAMA Intern Med. 2016 Published online January 25, 2016. Accessed February 17, 2016.

    Machado G.C., Maher C.G., Ferreira P.H., et al. Efficacy and safety of paracetamol for spinal pain and osteoarthritis: systematic review and meta-analysis of randomised placebo controlled trials. BMJ. 2014;350:h1225 Accessed February 25, 2016.

    Mularski R.A., White-Chu F., Overbay D., et al. Measuring pain as the 5th vital sign does not improve quality of pain management. J Gen Intern Med. 2006;21:607–612.

    Onysko M., Legerski P., Potthoff J., Erlandson E. Targeting neuropathic pain: Consider these alternatives. J Fam Pract. 2015;64(8):470–475.

    Partners Against Pain. Gender and pain management. Available at http://www.partnersagainstpain.com/hcp/pain- management-resources/gender-pain.aspx [accessed 6.22.15].

    Paulozzi L.J., Jones C.M. Vital signs: Overdoses of prescription opioid pain relievers—United States, 1999–2008. MMWR.

    2011;60:1487–1492.

    Traynor L.M., Thiessen C.N., Traynor A.P. Pharmacotherapy of fibromyalgia. Am J Health Syst Pharm. 2011;68:1307–1319.

    Volkow N.D., Swanson J.M., Evins A.E., et al. Effects of cannabis use on human behavior, including cognition, motivation, and psychosis: A review. JAMA Psychiatry. 2016;73(3):292–297.

    Whiting P.F., Wolff R.F., Deshpande S., et al. Cannabinoids for Medical Use: A Systematic Review and Meta-analysis. JAMA. 2015;313(24):2456–2473.

    1  Not FDA approved for this  indication.

    7  Available as dietary supplement.

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About Genomic Medicine UK

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