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The Impact of Pharmacology for PAIN:  The National Center for Health Prescribing Controlled Statistics estimates that 32.8% of the U.S. population has persistent pain

 ~94 million U.S. residents have episodic or Substances persistent pain (1 in every 5 adults)

Judith A. Kaufmann, Dr PH, FNP-BC  Treatment for rarely Robert Morris University results in complete relief and full functional recovery

 Of patients diagnosed with chronic pain and treated by a PCP, 64 percent report persistent pain two years after treatment initiation

US Statistics: The Alarming Impact of Pain Facts  Pain ranks low on medical tx priority  Americans constitute 4.6% of world’s  only 15% of primary care physicians report that they "enjoy" treating patients with chronic pain population-but consume ~ 80% of world’s  Dahl et al., and Redford (2002) found that patients supply said they fear dying in pain more than they fear death  Americans consume 99% of world supply of hydrocodone  Pain over the past 10 years has been designated the 5th vital sign  Between 1999 and 2006, the number of people >age 12 using illicit prescription  Pain is 3rd leading cause of absence pain relievers doubled from 2.6 to 5.2 from work million

 2006 National Survey on Drug Use and Health (NSDUH)

Are we the Pushers? Can we be found guilty?

 Since 1999, opioid poisonings on  55.7% of users obtained drugs from a death certificates increased 91% friend or relative who had been prescribed the drugs from 1 provider  During same period, fatal heroin and cocaine poisonings increased 12.4% and 22.8%  19.1% of users obtained their drug directly respectively from 1 provider  In 2008, 36,450 opioid deaths were  1.6% reported doctor shopping reported  3.9% reported purchasing drugs from a  CDC, 2011 dealer  Male:female ratio = 1.5:1 but death rate for females ia 20x higher than males

1 Is opioid abuse a recent Classifications of Pain phenomenon?  Acute V. Chronic

 Pain relief and euphoric  Acute pain has easily defined onset and is effects of were transient well known to Sumerians • Occurs only between the time of tissue injury and and Egyptians (4000- tissue recovery

2000 BC)  Chronic pain persists or recurs over extended  Ancient Greeks first period of time and interferes with patient’s identified and used the functioning latex of immature seed • Associated with depression and dysfunction and capsules of the poppy diminished quality of life flower derived from opium • Much more complex and difficult to treat — (Papaver somniferum).

Classifications of Pain Nociceptive pain

 Nociceptive V. Neuropathic  Somatic nociceptive: originates in skin or skin structures  Nociceptive: Primary sensory neurons • Stimulation of pain receptors () located  Well localized to specific area in the body throughout the body • e.g., tendinitis, post surgical pain • Respond to noxious stimuli- thermal, mechanical, chemical  Visceral nociceptive: originates in the internal  Can be further subdivided into somatic and organs as a result of infiltration, compression, visceral pain stretching  Difficult to localize and often referred to distant sites • e.g., MI pain, pancreatic pain, GB pain  Both types of nociceptive pain respond to both non steroidal anti-inflammatories and opioids

Chemical Mediators of Pain Chemical Mediators of Pain

 Initiate or perpetuate continuing stimulation of small pain conducting fibers  :

and • Influences pain perception  Polypeptides:

, prostaglandins (PG), and substance P  Blocking any of these substances minimizes pain signals and the perception of pain  Targets for pharmacologic agents to control pain

2 “just don’t inhale…”: Pain-Modulating receptors receptors and endogenous have  Tolerance for pain varies person-person become a focus for research on pain regulation  May be due to individual production of endogenous pain relieving substances  Two cannabinoid receptors : • CB1-expressed in the brain, SC, and  and • β-endorphin is the most important endogenous analgesic sensory neurons identified to date • CB1 receptors appear to be responsible  Released by the pituitary in response to painful for the euphoric and anticonvulsive stimulus or stressor effects of  Found in bloodstream and in specific neurons • CB2-expressed in non-neural tissue and  Once released, β-endorphin stimulates inhibitory immune cells, including microglia neuronal receptors (opioid receptors) • Microglia: glial cells that acts as first line of active  The mu (μ) (an ) inhibits the immune defense in the CNS transmission of pain signals to and from the higher • CB2 receptors appear to be responsible for brain centers the anti-inflammatory and possibly other  These same μ receptors are stimulated by morphine- therapeutic effects of cannabis like drugs (opioids)

Blocking the endocannabinoid Pain receptors and Their Biologic system: Lesson from Rimonabant Effects Receptor Biologic response to Stimulation  Was in Phase III clinical trials for treatment MU (μ) Respiratory depression, physical of obesity depression, tolerance, ,  Trials discontinued due to unexplained euphoria, miosis suicides in treatment group Kappa (κ) Spinal level analgesia and sedation  Found that drug also blocked pleasure without respiratory depression, pupil center in the brain constriction (miosis) Sigma (σ) Vasomotor stimulation, psycomimetic effects, + miosis

Neuropathic Pain Perception

Pain  There are two ways for nociceptive information to reach the CNS  Originates from compression or injury to  the neospinothalamic tract for "fast spontaneous peripheral nerve fibers or to the central pain" • Fast pain is felt within a .10 second of application of the pain nervous system stimulus • sharp, acute, prickling pain felt in response to mechanical and  Describes as burning, shooting, electrical thermal stimulation • Aδ fiber (A delta-fibers) terminate on the dorsal horn of the • Can be dermatomal or non dermatomal in distribution where they synapse with the dendrites of the neospinothalamic tract.  E.g., post herpetic , trigeminal neuralgia,  paleospinothalamic tract for "slow increasing pain". diabetic neuropathy • Slow pain is transmitted via slower type C fibers • neurons terminate throughout the brain stem (thalamus,  Less responsive to or anti- medulla,pons and midbrain inflammatories • Slow pain is stimulated by chemical stimulation  poorly localized  May require antidepressants, anticonvulsants  described as an aching, throbbing or burning pain

3  When nociceptors become sensitized (ie, more responsive), their thresholds are reduced, thus causing (ie, hypersensitivity to pain) The CNS discards more than 99%  , , leukotrienes, of all incoming signals as prostaglandins, serotonin, and K+ that are often irrelevant released near damaged or dying cells sensitize nociceptors.  K+ activates the nociceptors.  Substance P is also released from nociceptors through an causing hyperalgesia, vasodilatation and increased capillary permeability  Glutamate may be co-released with substance P from C-fibre terminals

The gate-control hypothesis of pain Structural Brain Changes

 Pain transmission is suppressed by signals in thick myelinated  Short term opioid use has been associated afferents with gray matter changes in patients with  Pain sensation is enhanced by signals in thin afferents chronic pain

 Inhibitory interneurons(in dorsal  LONG TERM gray matter changes horn of the SC) perform the gate- correlated with the dose of morphine after control through a special type of only one month of use pre-synaptic inhibition called primary afferent depolarization  Changes persisted an average of 4.7 months (PAD), and the receptors on the after drug stopped cell body of the secondary neuron • Younger, et al., 2011 is the gate

Recommended Order of Treatment for Pain Severity of Pain Agents Comments

Mild to Moderate Acetaminophen, Maximum doses should be ASA, NSAIDs used before proceeding to opioids Opioid Analgesics Moderate to Severe Codeine, Usually prepared in hydrocodone, combination with non- oxycodone, opioid analgesics BLACK BOX WARNING: Use Cautiously. propoxyphene Side effects limit dosing Can lead to “pain in the …” for the Severe Morphine, MSO4 is the gold standard oxycodone, in all patients ~ including provider hydromorphone, the elderly fentanyl, meperidine

4 General Overview Analgesic Effects

 Bind with one of four opiate receptors   Analgesic effects associated with binding to μ Opioid analgesics are: and κ receptors • Full agonists= morphine, hydrocodone,  Associated with unexplained loss, hydromorphone, fentanyl, methadone, misplacement codeine, oxycodone • Partial agonist-antagonist =pentzocine (Talwin)  Frequently the drug of choice for dogs  Can precipitate withdrwawal • Weak agonist= (Ultram)  Drugs most often flushed down the toilet  Activation of μ opioid receptors is associated with analgesia and undesired effects  Difficult names for patients to recall  Respiratory depression, euphoria, mydriasis, • Kaufmann, et al., 1988-2012 sedation, , tolerance  Agonist activity at the opiate μ- or κ-receptor can result in analgesia, initial miosis followed by mitosis, and/or decreased body temperature

Opioids are classified by their ability to stimulate (agonist) or block (antagonist) Opioid Action opioid receptors  Opiate agonists alter perception of and emotional response to pain  Kappa receptor stimulation produces  Precise mechanism of action has not been analgesia, dysphoria and respiratory fully elucidated distress  opiate agonists act at several CNS sites,  Stimulation of delta opioid receptors involving several systems produces analgesia without respiratory to produce analgesia distress  Pain perception is altered in the spinal cord and higher CNS levels

General Pharmacokinetic Precepts Opioid Action of Opioids  Hepatically metabolized to active and inactive  Opiate agonists do not alter the threshold metabolites or responsiveness of afferent nerve  Active metabolites differ with each drug

endings to noxious stimuli, nor peripheral  E.g., meperidine is metabolized to active metabolite, nerve impulse conduction normperidine, that accumulates and causes seizures  Opiate agonists act at specific receptor  Analgesic effects begin 30-60 minutes and binding sites in the CNS and other tissues; reach peak effect in 1-2 hrs opiate receptors are concentrated in the  Duration of action varies with each drug  Unlike NSAIDs, pure opioid agonists do NOT have a limbic system, thalamus, striatum, ceiling effect , midbrain, and spinal cord • Increased dosage produces increased analgesia  Eliminated in the urine

5 November 19, 2010 Cellular Mechanism of Action

 FDA removed propoxyphene (Darvon/Darvocet  Binding of opioid to receptor: and generic) from the US market  Decreases entry into cells allowing increased  Decision was made based on new clinical data time for channels to remain closed showing that the drug puts patients at risk for  Activation of opioid receptors leads to: potentially serious or even fatal heart rhythm  K+ efflux and increases the negative charge of the abnormalities cell membrane→

 An estimated 10 million patients have used these  failure of calcium channels to activate with net result products of decrease in release of , serotonin and nociceptive (Substance P)→  Changes to the heart's electrical activity are not cumulative  Blockage of nociceptive transmission

 once drug is d/c’d, the risk is gone

Morphine: Prototype of Opioids Additional Actions

 Low cost, well studied  Depression of cough reflex  Distributed throughout the body • Receptors for antitussive action  Crosses BBB in small amounts appear to differ from analgesia  Least lipophilic of all opioids receptors  Plasma T1/2 ~ 3 hrs d/t nearly complete  Treatment of intractable metabolism in the liver  Multiple routes of administration and duration of  Treatment of acute pulmonary edema effect (short acting, immediate release, • ?d/t vasodilatory effect sustained release)  Indicated for severe pain

 Best for dull, chronic pain regardless of anatomic source

Adverse reactions Contraindications/ Precautions

 Emesis without unpleasant sensations  Respiratory depression  Hypotension and bradycardia  Acute or severe bronchial asthma or hypercarbia  Histamine release→urticaria, sweating,  Use with extreme caution in patients with COPD or cor pulmonale flushing  Hormonal effects:  Known or suspected paralytic ileus • Lowers testosterone and cortisol levels  Head Injury and Increased Intracranial Pressure:  The respiratory depressant effects of morphine (with CO2 retention • Increases prolactin and growth and secondary elevation of CSF pressure) may be markedly hormone release exaggerated in the presence of head injury, other intracranial lesions, or preexisting increase in intracranial pressure • Increases antidiuretic hormone→urinary retention

6 Codeine and Derivatives Notes on Other Opioids

 Indicated for tx of mild-moderate pain  Meperidine (Demerol) is a potent  Excellent oral bioavaliability but only 1/10 as anticholergic agent potent as MSO4  Causes dry mouth, blurred vision and  Much less addictive and produces little euphoria tachycardia, ectopic beats  Less intense adverse effects except in children • Can cause respiratory depression  Active metabolite is proconvulsant and  Partially metabolized into morphine hallucinogenic

 Accounts for analgesic effect  Unlike MSO4, not associated with prolongation  Often used in combination with ASA of labor • Increased pain relief d/t inhibition of prostaglandins + inhibition of nociceptive transmission • Increases uterine contractions

Oxycodone hcl Hydrocodone

 Pharmacokinetics  Always compounded with acetaminophen

 Absorption  Toxicity related to high doses of • High oral availability due to low presystemic or first- acetaminophen pass metabolism. • Adults should not take more than 4000 mg/day • The immediate-release oral bioavailability is 100%. • Liver disease < 2000mg/day The oral bioavailability is 60% to 87%  Overdose of acetaminophen is due to toxic • Peak plasma concentration increased by 25% with a high fat meal metabolite that can cause acute liver necrosis

  Metabolism Consider when single ingestion exceeds 140 • Extensively metabolized in the liver to noroxycodone to 200 mg/kg or chronic use exceeds 10 days (a major metabolite) and oxymorphone, at usual doses.

Notes on Other Opioids Opiate Dependence  Hydromorphone is 8x more potent than  Repeated opioid use results in adaptations of MSO4 noradrenergic locus ceruleus (located in the pons) that are associated with physical  Indicated for severe pain and in high doses dependence and withdrawal, based on study in for pain relief in opioid addicted patients mice and rats (J Neuroscience 2005; 25(25):  Fentanyl is 80-100x more potent than 6005) MSO4  Repeated opiate use may alter neurotransmitter  Excellent for post op pain after the immediate and systems that regulate post op period d/t respiratory depression response and drug seeking behavior (J • In lozenge form (to induce ) and Neuroscience 2002, 22(9): 332) transdermal (, chronic pain)  Physical dependence usually occurs 1-4 weeks  Far more intense SE’s than with MSO4 after continuous opioid use  Potentially teratogenic and possibly implicated in SIDS

7 Chromosome 17 Harbors Opioid Addiction Opioid Dependence Genes  An estimated 898,000 adults in the United  Twin studies also suggest that certain genes States are opioid dependent (AAFP, 2006) may increase the risk of opioid addiction without  Methadone has been the treatment of choice in affecting the likelihood of addiction to other the United States drugs.

 Methadone maintenance programs typically  Gelernter, J., et al. Genomewide linkage scan for opioid have stringent entrance criteria, long waiting dependence and related traits. American Journal of Human Genetics 78(5):759-769, 2006. lists, and primarily are located in urban areas  Candidate genes impact in a variety of ways,  Only 14% of patients who are addicted to opioids are treated in traditional methadone including statistical studies to determine the clinics. effects of eliminating, activating, or inactivating the genes on animals' responses to drugs.

Treatment Options for Opioid Methadone Abuse  Methadone  In pregnant heroin-addicted women, substitution  Mu recptor agonist with delayed onset of with methadone associated with fewer LBW action and longer half life newborns and fewer learning/cognition problems  Analgesic profile and potency and SE’s in children similar to MSO4 • Longer duration of action and better oral  Methadone has similar addiction potential to bioavailability opioids and heroin • Useful in treatment of addiction

 Once tolerance develops, has little impact on mood, judgment, and psychomotor skills

Methadone Side Effects Buprenorphine (Suboxone)  Common:  The Drug Addiction Treatment Act of 2000  Insomnia, restlessness, nervousness, drowsiness, enabled physicians to provide office-based weakness, /nausea, diarrhea, constipation, dry treatment for opioid addiction using mouth, changes in appetite, decreased libido, male buprenorphine, a partial mu-opioid receptor impotence and anorgasmia agonist  Sudden withdrawal:  Clinical studies indicate buprenorphine effectively manages opioid addiction  , irritability, insomnia, hypertension, increased perspiration, rigors, , and  Buprenorphine is more effective than placebo for managing opioid addiction but may not be arthalgias, muscle spasms and an overall "sick" feeling. superior to methadone • w/d occurs 24 and 48 hours after stopping  Family physicians are required to complete methadone and increase in intensity over the next 6 eight hours of training before they can days prescribe buprenorphine for opioid addiction.

8 Mechanism of Bupernorphine Message to Providers: It may be Action time to  Partial agonist at the mu receptor

 Limits the intense high of other opioids (ceiling effect)

 Alters mood but with less intensity  Tightly binds to mu receptor

 prevents other opioids from accessing the receptor site

 Displaces other opioids from mu receptors • Buprenorphene taken while on other opioids will casue rapid withdrawal symptoms

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