MEDICAL TOXICOLOGY:OPIOID ADDICTION & TOXICITY

Why take opioid?Relief of severe painUphoric effects (drug of abuse)

Which opioid for chronic medication?Preferable: an orally active, slow-onset opioid with a long duration of action.(WHY? reduce the likelihood of producing euphoria at onset and withdrawal symptoms as the medication wears off) METHADONEControlled-release oral MORPHINEControlled-release OXYCODONEHeroin is the most frequently abused opiate. There is no legal supply of heroin for clinical use

Oxycodone

high-dose produces euphoria that is sought by opiate abusersthe long-acting version of oxycodone has been formulated to release slowly; change a short-acting opioid into a long-acting one. Unfortunately, this mechanism can be subverted by breaking the tablet and making the full dose of oxycodone immediately available.diversion of oxycodone to illicit traffic

WHICH OPIOIDS BEING ABUSED?** Heroin** Oxycodone

Morphine PethidineFentanyl

Mechanism at cellular levelAll opioid receptors are G-protein coupled receptors.Actions:1. Close voltage-gated Ca2+ channels on presynaptic nerve terminals therefore reduce transmitter release (glutamate, acetylcholine, noradrenaline, serotonin, substance P)

2. Cause opening of K+ channels; hyperpolarised; inhibit postsynaptic neurons.

Outcome: Inhibit neuronal activities

Important note on effects of opioidInjection of a heroin solution produces a variety of sensations described as warmth, taste, or high and intense pleasure ("rush") often compared with sexual orgasmNormal volunteers with no pain may report the effects as unpleasant because of side effects such as nausea, vomiting, and sedation.Patients with pain usually do not develop abuse or addiction problems.Opioids should never be withheld from patients with cancer out of fear of producing addiction.

HEROIN ABUSEBefore 1990: street heroin in the U.S. was highly diluted: Each 100-mg bag of powder ~4 mg heroin (range: 0-8 mg) (the rest was filler such as quinine) Mid-1990s: street heroin reached 45-75% purity in many large cities, some samples as high as 90%. Whereas heroin previously required intravenous injection, the more potent supplies can be smoked or administered nasally (snorted), making the initiation of heroin use accessible to people who would not insert a needle into their veins.

Effects of Heroinrapid onset,

TOLERANCEDevelops early to the euphoria-producing effects of opioids. Also tolerance to the respiratory depressant, analgesic, sedative, and emetic properties.Heroin users tend to increase their daily dose If a supply is available, the dose can be increased progressively 100 times. Overdose is likely to occur when potency of the street sample is unexpectedly high or when the heroin is mixed with a far more potent opioid, such as fentanyl (sublimaze, others).

Street heroin users very high mortality rate Early death comes from involvement in crime to support the habit from the uncertain dose, purity, and even identity of what is purchased on the street from serious infections associated with nonsterile drugs and sharing of injection paraphernalia commonly acquire bacterial infections producing skin abscesses; endocarditis; pulmonary infections, especially tuberculosis; and viral infections producing hepatitis C and acquired immune deficiency syndrome (AIDS).

Toxicity of OOPIOID Acute overdoserespiratory depression pinpoint pupils (miosis) coma Treatment1. establish adequate ventilation2. give OPIOID antagonist (naloxone)

Symptoms of OD Awake but no responseLimp bodyPale in colorSlow or no pulseBlue fingertips or lipsShallow breathingPassed outChocking or gurgling noicevomiting

OOD MgmtInitial focus on airway and breathingAdminister IV naloxoneApneic pts and pts with extremely low RR should be ventilated by bag-valve mask attached to O2 to reduce ALI.Apneic pts should receive 0.2-1mgPts in cardiopulmonary arrest should be given minimum of 2mgWhen spontaneous ventilations are present, give initial dose of 0.05mg and titrate upward every few minutes until RR >12.The goal of naloxone is NOT level of consciousness, but adequate ventilation.In the absence of signs of opioid withdrawal, there is no maximum safe dose; if clinical effect does not occur after 5-10mg, reconsider your diagnosis.

OOD Mgmt (cont)Naloxone InfusionIf hypoventilation recurs following initial bolus, give additional boluses to restore adequate ventilation. When ventilation is adequate, an infusion may be initiated at a rate of 2/3 the total dose of naloxone needed to restore breathing, delivered every hourIf respiratory depression develops despite an infusion, administer naloxone bolus (using the original bolus dose) and repeat if necessary until adequate ventilation returns, then increase the infusion rate.

OOD Mgmt (cont)If the clinician overshoots the appropriate dose in an opioid-dependent individual, withdrawal will occur. Manage expectantly, not with opioids.Activated charcoal and gastric emptying are almost never indicated in opioid poisoning. The large volume of distribution of opioids precludes removal of a significant quantity of drug by hemodialysis. In most cases, the pt may be discharged or transferred for psychiatric evaluation once respiration and mental status are normal and naloxone has not been administered for 2-3 hrs.

TREATMENT OF OPIOID DEPENDENCEthe first stage of treatment addresses physical dependence and consists of detoxification The opioid-withdrawal syndrome is very unpleasant but not life-threatening. begins within 6-12 hours after the last dose of a short-acting opioid and as long as 72-84 hours after a very long-acting opioid medication.

Characteristics of Opioid Withdrawal

SYMPTOMSRegular withdrawalCraving for opioidsRestlessness, irritabilityIncreased sensitivity topainNausea, crampsMuscle achesDysphoric moodInsomnia, anxietyProtracted withdrawalAnxietyInsomniaDrug craving

Characteristics of Opioid Withdrawal

SIGNSRegular withdrawal

Pupillary dilationSweatingPiloerection ("gooseflesh")TachycardiaVomiting, diarrheaIncreased blood pressureYawningFeverProtracted withdrawalCyclic changes in weight,pupil size, respiratorycenter sensitivity

WITHDRAWAL SYNDROMEHeroin withdrawal is brief (5-10 days) and intense. Important note **the withdrawal syndrome does not end in 5-7 days. There are subtle signs and symptoms (protracted withdrawal syndrome) that persist for up to 6 months. during this phase, outpatient drug-free treatment has a low probability of successMethadone withdrawal is slower in onset and lasts longer. Protracted withdrawal also is likely to be longer with methadone.

METHADONE REPLACEMENTmost successful treatment for heroin addictionPatients who relapse repeatedly during drug-free treatment can be transferred directly to methadone without requiring detoxification. The dose of methadone must be sufficient to prevent withdrawal symptoms for at least 24 hours.

BUPRENORPHINE (SUBUTEX)a partial agonist at opioid receptors represents a major change in the treatment of opiate addiction. produces minimal withdrawal symptoms when discontinued has a low potential for overdose a long duration of actionand the ability to block heroin effects.

Buprenorphine-Naloxone combination (SUBOXONE) Buprenorphine has the potential to be dissolved and injected (abused). Explain rationale for giving SUBOXONE...

NALTREXONEAnother pharmacological option is opioid antagonist treatmentAn antagonist with a high affinity for the opioid receptor; it will competitively block the effects of heroin or other MOR agonists. Naltrexone has almost no agonist effects of its own and will not satisfy craving or relieve protracted withdrawal symptoms. For these reasons, naltrexone treatment does not appeal to the average heroin addict but it can be used after detoxification for patients with high motivation to remain opioid-free.

OPIOID DEPENDENCEPhysical dependence (withdrawal symptoms)

Psychological dependence

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