List Three Mechanisms by which Chronic Opioid Therapy Can Worsen Pain C.L.I.P.S. Neurobiology of Pain and Addiction (1) Physiology of Pain Pain can either be adaptive or maladaptive Adaptive pain is life-saving, protects us from injury and promotes healing Maladaptive pain (chronic) represents neurologic system pathology Pain can be nociceptive (either somatic or visceral nerves being triggered by noxious stimuli), or neuropathic (arises from malfunction or damage to neurons) Pain signals travel from nociceptors through dorsal column of spinal cord to thalamus and then to somatosensory cortex where it reaches consciousness Pain signals are modulated in the cortex with descending pathways involving multiple brain structures. These pathways interact with opioid, serotonergic and noradrenergic systems which can amplify or dampen pain signals. Physiology of Substance Use Disorders Stimulants like cocaine, methamphetamine and nicotine increase levels of dopamine, norepinephrine and serotonin. Chronic use leads to altered receptor sensitivities in these reward pathways, tolerance and increase in drug cravings. Opiates also trigger the dopaminergic reward pathways but involve different brain structures that are activated by mu receptors. The physical dependence and withdrawal from chronic opioid use is mediated by norepinephrine which is separate from reward pathways. Alcohol, benzos and barbiturates increase levels of GABA, a CNS depressant. Chronic cellular changes from long-term use involve changes to endogenous opioid systems which leads to the addiction and physical dependence & withdrawal. This is why naltrexone reduces ETOH cravings. List Three Mechanisms by which Chronic Opioid Therapy Can Worsen Pain Tolerance –same amount of drug creates less analgesia Intermittent withdrawal – brain experiences opiate withdrawal as worsening of pain Hyperalgesia – nociceptive sensitization causing increased sensitivity to painful stimuli or even non-painful stimuli (allodynia) Updated 1/16 E. Lund

Neurobiology of Pain and Addiction (2) C.L.I.P.S. Neurobiology of Pain and Addiction (2) Why is this important? 35% of primary care patients have chronic, non-cancer pain High rates of co-morbidity with mental health disorders, adverse life events, substance use disorders and chronic pain Opioids most commonly Rx’d treatment for chronic pain but not effective long term, worsen function, cause physical dependence, and in some addiction Pharmacologic Alternatives to Opioids in Patients with Chronic Pain Non-Opioid Analgesics – aspirin, acetaminophen, NSAIDS Tramadol – targets mu receptor weakly but also serotonin, norepinephrine Alpha 2 adrenergic agonists – clonidine Antidepressants – TCA’s, SNRI’s (NNT 2-3 for neuropathic pain) Antiepileptic Drugs – gabapentin, pre-gabalin, carbamazepine Muscle relaxants – mostly act through sedation, caution w/ other drugs Topical analgesic agents – lidocaine (localized neuropathic pain), capsaicin (moderate to poor efficacy for neuropathic pain), topical NSAIDs (moderate improvement in acute MSK pain, less evidence for chronic pain) Treating Neuropathic pain – 1st line either antiepileptic drugs or TCA’s. SNRI’s are either 1st or 2nd line. Opioids only after these fail with equivocal evidence for efficacy in short term (<12wks) based on 2013 Cochrane review. Treating Nociceptive Pain – 1st line non-narcotic analgesics or topical agents. 2nd line TCA’s. 3rd line Opiates. Chronic use of opioids only in pts at low risk for addiction and who have failed non-narcotic analgesics in combo with antidepressants. Always use adjunctive non-pharma txs like PT, massage, etc. What TCA’s are available on $4 formulary at Target/Walmart and through 340b program? Amitriptyline, Nortriptyline What is the price of 90 tabs of Gabapentin (any strength) under 340b program? $20/month