Analgesics II: Centrally Acting Analgesics - Opioids

What are opioids?

-all drugs with morphine-like actions are described as opioids

-opioids were originally derived from the opium poppy (papaver somniferum)

>has 25 alkaloids (nitrogenous chemicals from plants that has physiological effects on ppl)

>> only 2 have analgesic effects = morphine & codeine

opiate

term used to refer to drugs derived from the opium poppy

(ex: morphine)

*doesn't include synthetic opioids such as fentanyl

opioid

refers to any substance w/ morphine-like activity including natural, semi-synthetic, & synthetic opioids

Classification of Alkaloids

-natural opium alkaloids

>Morphine

> Codeine

-semisynthetic opiates

>Heroin (diacetylmorphine)

>pholcodeine

-synthetic opioids

>pethidine (meperidine)

> fentanyl, alfentanil, sufentanil, remifentanil

>methadone

>dextropropoxyphene

>Tramadol

-endogenous opioid peptides --> endorphins, enkephalins, dynorporphins, & endomorphins made naturally in the body

Natural Opium Alkaloids

-morphine

-codeine

Semisynthetic opiates

-diacetylmorphine (heroin)

-pholcodeine

synthetic opioids

-pethidine (meperidine)

-fentanyl, alfentanil, sufentanil, remifentanil

-methadone

-dextropropxyphene

-tramadol

endogenous opioid peptides

opioids naturally made in the body ==> reason you don't feel pain immediately after a major accident/injury

-endorphins

- enkephalins

-dynorphins

-endomorphins

How do opioids work (in general)?

When opioids bind to receptors (u, k, delta) they alter the interpretation & emotional reaction to pain stimulus ==> doesn't eliminate pain, just reduces the bodies response to pain so we don't feel it

opioid mu receptors (u)

opioid receptors located in the brain & spinal cord to elicit analgesia, respiratory depression, euphoria, addiction , & blocks all pain messages

opioid kappa receptors (K)

opioid receptors located in the brain & spinal cord that elicit analgesia, sedation, & blocks all non-thermal pain messages

opioid delta receptors

opioid receptors located in the brain that elicit analgesia, anti-depression, & dependence

What are some things to keep in mind when prescribing opioids?

-no dose limit or ceiling dose for analgesic effects

-lack anti-inflammatory & anti-pyretic

-more problematic side effects that limit use --> primarily CNS depression

-drug seeking behavior, abuse, tolerance, & physical dependence development

-subject to the Controlled Substances Act --> limitations on prescribing = Schedule II (potential to create addiction & dependency)

True or False: Opioids have a limited range of efficacy

False ==> has wide range of efficacy

ex: Fentanyl way more efficacious than codeine

Why are opioids used in combination analgesics?

combine the peripheral action of quick acting & shorter dusration aspirin or tylenol with the slow onset & longer acting central pain relieving of the opioid

*provides the pain relief of a higher dose of the opioid component w/o the side effects associated with the use of the higher dose

What are the side effects opioids?

-respiratory depression

-sedation

-euphoria

-pinpoint pupils (miosis)

-itch

-muscle rigidity

-bradycardia --> w/ high doses

-vasodilation

-hypotension

-urinary retention

-nausea & vomiting

-delayed gastric emptying

-constipation

-addiction

-dependency

-withdrawal

-tolerance

*usually dose-related & occur regardless of which opioid is used

True or False: Heroin has more side effects than morphine.

False ==> all opioids have the same number of side effects; dose of opioid effects the number & intensity of side effects

Opioid Tolerance

-increased doses of opioid needed to produce the same pharmacological effect

-selective --> mainly effects the depressive effects like analgesia & respiratory depression (but not the stimulatory effects like miosis)

-cross -tolerance develops bwtn different narcotics

What are some contraindications to consider for opioid use?

-lethal to combine w/ CNS acting drugs --> don't prescribe to pts on anti-depressants, antipsychotics, sedatives, etc

-elderly have increased sensitivity to CNS effects & constipation

-can reinstate dependence in recovering/recovered drug abuser

-can't operate dangerous machinery or automobiles

-combined w/ alcohol greatly increases the risk of drowsiness, impaired thinking, & unconsciousness

-some pts are allergic/hypersensitive to some opioids (morph & cod)

-shouldn't give to pts w/ chronic respiratory disorders

-shouldn't give to pts w/ liver disease

-shouldn't give to pregnant pts (Ops are category C)

-shouldn't give to patients w/ known bowel obstruction

Why is opioid use increase the risk of prescription misuse?

-family or personal history of substance abuse

-young age

-frequent contact w/ high-risk individuals or environments

-smoking cigarettes & regularly using other substances that lead to dependence

-history of childhood abuse

-previous drug &/or alcohol rehabilitation

Morphine

pure opioid; powerful mu agonist

-schedule II drug

-varied formulations--> oral, IV, intramuscular, subcutaneous

>oral immediate release mixture tabs

>oral sustained release

-metabolites = morphine-3- glucuronide (M3G) & morphine 6- glucuronide (M6G)

codeine

pure opioid that's a mu agonist indicated for mild to moderate pain ==> pro-drug converted to morphine via CYP2D6

-Schedule II

-CYP2D6 is polymorphic so 7-10% of population unable to convert codeine to morphine (no analgesic effect) & some ppl are rapid converters get toxicity easily

-can trigger allergic reactions --> stimulate histamine release --> rash & pruritis

-Mostly used in combination form w/ tylenol in dentistry

How does Prozac & Paxil affect codiene?

inhibit CYP2D6 (that coverts cod to active form morphine) ==> results in no pain relief

True or False: Codeine can trigger allergic reactions

True ==> can trigger histamine release leading to rash & pruritis

*substitute with another opioid not structurally related to codeine (ex: propoxyphene or meperidine)

Vicodin

combination opioid that contains hydrocodone + acetaminophen in a very of strengths

-most commonly prescribed analgesic by dentists for moderate to severe pain

-Schedule II drug

-max dosing dependent on acetaminophen --> toxicity usually due to heptatoxicity

Hydrocodone/Oxycodone

synthetic opioid that has greater analgesic effect than codeine but causes less nausea & vomiting

-schedule II

*hydrocodone metabolized to active form hydromorphone via CVP2D6

tramadol (ultram)

opioid that has opioid & non-opioid properties

-not a strong analgesic --> used for mild to moderate pain

- non-opioid effects are via noradrenaline & serotonin pathways

-active metabolite (M1) has mu receptor affinity

-schedule IV drug = low potential for abuse & dependency

Schedule II Drugs

drugs with high potential for abuse & dependency

Schedule IV Drugs

drugs w/ low potential for abuse & dependency

Ultracet

combination form opioid tramadol + acetaminophen ==> rapid onset analgesic via acetaminophen & long duration opioid analgesic via tramadol

-schedule IV drug

-dentistry use = for moderate to moderately severe acute dental pain

-reduced incidence of opioid related side effects such as constipation, nausea, dizziness, & somnolence

-avoid seizure prone patients

OxyContin

oxycodone HCl; time release oxycodone preparation indicated for the management of severe pain

-schedule II

-metabolized by CYP 3A4 ==> use w/ CYP3A4 will result increased oxycodone plasma levels--> increased/prolonged adverse drug effect--> cause potentially fatal respiratory depression

-must swallow whole --> can't chew or crush b/c it will result in rapid release & adsorption of a potentially toxic dose of oxycodone

Why can't you chew or crush OxyContin?

must swallow whole --> can't chew or crush b/c it will result in rapid release & adsorption of a potentially toxic dose of oxycodone

Combunox

the first & only Oxycodone + Ibuprofen combination long-lasting pain relief

fentanyl

very potent synthetic opioid

-short acting but lipophilic (fat soluble) drug which may result in accumulation

-schedule II

- available as schedule IV in skin patches & lozenges

methadone

synthetic opioid that's a very long-acting, strong mu agonist

*primarily used for Tx of addiction as a replacement therapy (used to wean pts off opioids) ==> stays in the system a longer time & tapper the patient down (doesn't have the rush effect)

meperidine (demerol)

opioid used for codeine allergic patients

*contraindicated in patients taking MAOIs (monoaminooxygenase inhibitors) b/c they cause increased formation of toxic metabolite normeperidine

What is the contraindication in prescribing meperidine to patients taking MAOIs?

Monoaminooxygenase inhibitors (MAOI) causes increased formation of meperidine's toxic metabolite normeperdine

buprenorphine

opioid that is a weak mu agonist & kappa antagonist

-25-50x more potent than morphine

-sublingual route

-postural hypotension is marked --> beware of giving during dental procedure (change from laying down to standing up can make pt fall out)

- metabolized by CYP3A4 --> subject to macrolide interactions

-used for in combo w/ Naloxone (as suboxone) to Tx opioid dependence ==> can be taken at home (unlike methadone)

Why is buprenorphine subject to macrolide interactions?

because buprenorphine is metabolized by CYP3A4 (macrolide must mess w/ this CYP somehow... not explained on slides)

Suboxone

buprenorphine + naloxone combination opioid used to Tx opioid dependence

*can be taken at home (unlike methadone)

naloxone (narcan)

opioid that displaces other opioids bound to opioid receptors

-given intranasally, intramuscular, subcutaneous, or intravenous injection

-used for

>opioid overdose

>diagnostic test for opioid addiction

> revert neonatal respiratory depression due to opioid use during labor

naltrexone

long-acting opioid that's used to treat alcoholism ==> helps stop craving for alcohol & drugs by actings indirectly on dopamine reinforcement pathways

*can also be used for rapid detox under anesthesia or sedation