Opioid pharmacology

HOSAM ATEF,MDHOSAM ATEF,MD

TerminologyTerminology

• Opioids: refers broadly to all compounds that work at the opioid receptors

• Narcotics: derived from the Greek word for stupor.– Once used to describe medications for sleep– Then used for opioids– Now a legal term for drugs that are abused

Opioid ReceptorsOpioid ReceptorsReceptors are located on the brain, spinal cord, gut,

peripheral nerves, and peripheral tissues• Mu (mu1 and mu2)

– Mediates the analgesic effects and most of the side effects of MSO4• Miosis, bradycardia, respiratory depression, constipation, histamine

release• Strong naloxone sensitivity

• Kappa (K1 and K2 and K3)• Sedation • Intermediate naloxone sensitivity

• Sigma• Mydriasis, delirium, dysphoria• ? No naloxone sensitivity

Opioid ReceptorsOpioid Receptors

EndorphinsEndorphins

• Identification of opioid receptors lead to the discovery of “endogenous morphines” endorphin (31 amino acids)- receptor endorphin (17 amino acids)- receptor– Leu-enkaphalin (5 amino acids)- receptor– Met-enkephalin (5 amino acids)- receptor– Dynorphin (17 amino acids)- receptor– Methorphamide (7 amino acids)- receptor


Presynaptic (75%)


Postsynaptic (25%)

Receptor AffinityReceptor Affinity

Classification of OpioidsClassification of Opioids

• Full Agonists - bind opioid receptors– MSO4

• Partial Agonists- bind opioid receptors at a lower level– Buprenorphine, etorphine

• Mixed agonist/antagonists - agonist effect at one receptor and antagonist effect at another receptor– Nalbuphine, butorphanol

• Agonist at the kappa receptor• Antagonist at the mu receptor

• Antagonists - bind to opioid receptors but have no activity– naloxone, naltrexone

Odd Case - TramadolOdd Case - Tramadol

• Works partially at the mu receptor– M1 metabolite

• Works partially at the norepinephrine receptors

• Additional unknown activity

• Where does it fit?

Opioid Therapy: Routes of Opioid Therapy: Routes of AdministrationAdministration

• Oral and transdermal—preferred • Oral transmucosal—available for fentanyl

and used for breakthrough pain• Rectal route—limited use • Parenteral—SQ and IV preferred and

feasible for long-term therapy • Intraspinal—intrathecal over epidural

generally preferred for long-term use

Metabolism of Codeine and MorphineMetabolism of Codeine and Morphine

Morphine MetabolismMorphine Metabolism

• Morphine– Metabolized to M3G and M6G (normorpine)

• Accumulates in renal failure and hepatic failure

• M6G has potential nocioceptive activity

• Significant polymorphism

– Potent histamine release

MorphineMorphine

• At a dose of 10mg per 70 kg body weight, gives relief in 70% of patients

• Available in short and long acting formulations

NMDA ReceptorNMDA Receptor

•Site of opioid tolerance

•NMDA antagonists reduce the incidence of tolerance to morphine

•Dexamathorphan•Methadone•Ketamine

Chemical Classes of OpioidsChemical Classes of Opioids

• Phenylpiperidines – Fentanyl

• Of all the opioids, has the least histamine mu-activity

• Least allergenic

– Meperidine• Only has a 2-3 hour duration• Metabolized to normeperidine

– Renally excreted– Causes seizures, myoclonus– Not reversible by naloxone

Serum LevelsSerum Levels

Transdermal FentanylTransdermal Fentanyl

Metabolism of FentanylMetabolism of Fentanyl

• No active metabolites, low histamine release

• Fentanyl is metabolized in the liver by to inactive metabolite– Macrolid antibiotics, antifungals, and protease

inhibitors) may lead to increased blood levels

• No first pass effect

Equianalgesic DosingEquianalgesic Dosing

Drug Oral Dose IV Dose Duration

morphine 30 mg 10 mg 3-4 hrs

hydromorphone 4-8 mg 1.5 mg 3-4 hrs

methadone 10-20 mg 6-12 hrs

codeine 300 mg 150 mg 3-4 hrs

oxycodone 20-30 mg 3-4 hrs

hydrocodone 30 mg 3-4 hrs

meperidine 300 mg 100 mg 2-3 hrs

All doses are approximate, and vary between authors.

• CNS– Analgesia, chemical dependency– Sedation/drowsiness– Dizziness, mental clouding, depression, mood

changes– Nausea, emesis (CTZ)– Antitussive (medullary cough center)– Disorientation, delirium, hallucinations,

agitation, restlessness, nervousness, seizures

Dose Related Opioid Side EffectsDose Related Opioid Side Effects

• Cardiovascular effects– Bradycardia (morphine, fentanyl)– Tachycardia (meperidine)– Cholinergic effects– Histamine release (fentanyl is the least)

• Dermatologic effects– Diaphoresis, flushing, pruritis, urticaria

• Genitourinary effects– Urinary retention, oliguria, vasopressin release



• Respiratory effects– CO2 tension response at the brainstem is decreased (decreased

minute ventilation, rate, tidal volume)

• Neuromuscular effects– Tremors (meperidine)

– Rigidity (fentanyl)

• Endocrine effects– Increased prolactin and growth hormone

– Decreased LH, testosterone, thyrotropin release

– Gonadotropin suppression (impotence), decreased libido


• Gastrointestinal effects– Xerostomia, decreased motility, increased

sphinchter tone– Nausea, emesis (CTZ), orthostatic hypotension– Increased vestibular sensitivity

Anticipate and Manage Side Anticipate and Manage Side EffectsEffects

• Constipation (opioid-induced bowel dysfunction)– Oral naloxone has been described– New agents such as methylnaltrexone and alvimopan


• Nausea and emesis– Promethizine, compazine

• Oral and rectal

– Metaclopromide– Subligual droperidol

• Itching– Not an allergic reaction– Reverses with low dose naloxone IV– Antihistamines– Reassure


• Respiratory Depression– Clinically significant respiratory depression is rare

when patients are in severe pain– Sedation precedes respiratory depression– Respiratory rate alone is not an indication of respiratory

function– Use naloxone sparingly

• Respiratory depression reverses before analgesia• Limit to doses of 100µg at a time• One amp (0.4mg) in 4cc NS, inject 1cc at a time• “You can always give more”

Respiratory DepressionRespiratory Depression

Opioid- Induced Androgen Opioid- Induced Androgen DeficiencyDeficiency

• Low serum levels of testosterone and:– Decreased libido– Erectile dysfunction– Fatigue– Depressed mood– Hot flashes

• 70% of men on long term opioids have have subnormal testosterone levels

Opioid ResponsivenessOpioid Responsiveness

• Opioid dose titration over time is critical to successful opioid therapy

• Goal: Increase dose until pain relief is adequate or intolerable and unmanageable side effects occur

• No maximal or “correct” dose

• Responsiveness of an individual patient to a specific drug cannot be determined unless dose was increased to treatment-limiting toxicity

Poor Opioid ResponsivenessPoor Opioid Responsiveness

• If dose escalation adverse effects– Better side-effect management– Pharmacologic strategy to lower opioid

requirement• Spinal route of administration• Add nonopioid or adjuvant analgesic

– “Opioid rotation”– Nonpharmacologic strategy to lower opioid

requirement

Opioid Therapy and Chemical Opioid Therapy and Chemical DependencyDependency

• Physical dependence

• Tolerance

• Addiction

• Pseudoaddiction

Opioid Therapy and Chemical Opioid Therapy and Chemical Dependency Dependency

• Physical dependence – Abstinence syndrome induced by administration of an

antagonist or by dose reduction

– Assumed to exist after dosing for a few days but actually highly variable

– Usually unimportant if abstinence avoided

– Does not independently cause addiction


• Tolerance– Diminished drug effect from drug exposure– Tolerance to side effects is desirable – Tolerance to analgesia is seldom a problem in

the clinical setting• Tolerance rarely “drives” dose escalation • Tolerance does not cause addiction


• Addiction– Disease with pharmacologic, genetic, and

psychosocial elements

– Fundamental features• Loss of control

• Compulsive use

• Use despite harm

– Diagnosed by observation of aberrant drug-related behavior


• Pseudoaddiction– Aberrant drug-related behaviors driven by desperation

over uncontrolled pain

– Reduced by improved pain control

– Complexities• How aberrant can behavior be before it is inconsistent with

pseudoaddiction?

• Can addiction and pseudoaddiction coexist?


• Risk of addiction: Evolving view– Acute pain: Very unlikely– Cancer pain: Very unlikely– Chronic noncancer pain:

• Surveys of patients without abuse or psychopathology show rare addiction

• Surveys that include patients with abuse or psychopathology show mixed results

Opioid Therapy and Chemical Opioid Therapy and Chemical DependencyDependency

• Addressing aberrant drug-related behavior– Strategies to respond to aberrant behaviors

• Frequent visits and small quantities

• Long-acting drugs with no rescue doses

• Use of one pharmacy, pill bottles, no replacements or early scripts

• Use of urine screens

• Coordination with sponsor, program, addiction medicine specialist, psychotherapist, others

Urine Drug Testing (UDT)Urine Drug Testing (UDT)

• Oxycodone and methadone do not appear on standard UDTs– Gas chromatography-mas spectrometry

• Codeine will appear as morphine

• Heroin will appear as morphine

Von Seggern RL et al. Headache 2004;44:4-47

State Specific Documentation State Specific Documentation RequirementsRequirements

• Arizona requires physicians to keep records such that they provide “sufficient information to allow another physician to assume care”.

• Colorado suggests physicians use a written contract.

• Mississippi requires physicians to keep patient records that include the presence of one or more recognized medical indications for the use of controlled substances.

• Pennsylvania requires physicians to have a specific statement regarding patient symptoms, the diagnosis and the specific directions given for controlled substances

Jennifer Bolen, The Legal Side of Pain

Opioid Therapy: ConclusionsOpioid Therapy: Conclusions

• An approach with extraordinary promise and substantial risks

• An approach with clear obligations on the part of prescribers– Assessment and reassessment– Skillful drug administration– Knowledge of addiction-medicine principles– Documentation and communication

QuestionsQuestions

A patient complains of inadequate analgesia and increases his use of his medication. This behavior may represent:

A. AddictionB. PseudoaddictionC. ToleranceD. All of the above

Answer: DIf the patient increases the medication despite the knowledge that he will be discharged, this may be addiction. If he increases the medication because of inadequate dosing, that may be pseudoaddiction. If he increases the medication because it is no longer effective, that may be tolerance.

Demerol (meperidine) should not be used for chronic pain because:

A. it is addictive

B. it is ineffective

C. the metabolite causes seizures

D. all of the above

All opioids can potentially be abused. Meperidine may be useful for acute pain. The metabolite normeperidine can cause seizures and can accumulate with chronic dosing, especially in renal failure.

Answer: C.

Strategies to reduce aberrant drug behaviors include:

1. Random urine drug screens

2. Narcotic contracts

3. No early refills

4. Opioid rotation

Random drug screens, narcotic contracts, and aggressive refill policies have been felt to help control aberrant drug behaviors. Opioid rotation tries to address the issue of drug tolerance.

Answer: A

30mg of MSO4 orally is equivalent to:

1. 30mg MSO4 IV

2. 20mg of oral oxycodone

3. 30mg hydromorphone IV

4. 20mg methadone

Answer: C

Although equipotent charts may vary, in general, 30mg of oral MSO4 is equivalent to 10mg MSO4 IV, 20mg of oral oxycodone, 1.5mg of IV hydromorphone, or 20mg of methadone.

Receptors involved in opioid activity include:

1. Mu

2. Sigma

3. Kappa

4. Gamma

Answer: A

Mu, sigma, and kappa are opioid receptors. Gamma is not.

The most appropriate type of opioid for chronic pain might be an:

A. Agonist

B. Agonist/antagonist

C. Antagonist

D. Antihistamine

Answer: A

Mixed agonists/antagonists are poor choices for chronic pain treatment. Antagonists counteract the effect of opioids. Antihistamines are not opioids.

Patients usually develop tolerance to all opioid effects EXCEPT:

A. Sedation

B. Pruritis

C. Constipation

D. Pain relief

Answer: C

Sedation and pruritis (due to direct histamine release) abate over time. Although tolerance to pain relief can occur, with long acting narcotics (especially methadone) it is less likely. Constipation, however, should be expected to be a problem for the entire length of treatment.

Once an opioid treatment is selected, titration upwards should continue until:

A. a ceiling is reached.B. addiction occursC. tolerance occursD. a balance between analgesia and side

effects is reached.Answer: D

There is no ceiling for opioids (other than the limitations of agonist/antagonists or APAP). The goal is to prevent addiction. Tolerance is less likely with long acting opioids. The goal is a balance between pain relief and intolerable side effects.

Examples of the phenanthrene class of opioid include all except:

1. Morphine

2. Fentanyl

3. Codeine

4. Meperidine

Answer: B

Morphine and codeine are phenanthrenes. Fentanyl and meperidine are phenylpiperidines.

If a patient is unable to tolerate oxycodone because of nausea, the least likely opioid to be tolerated would be:

A. FentanylB. PropoxypheneC. MorphineD. Methadone

Answer: CMorphine is in the same class of opioids (phenanthrenes) as oxycodone, but morphine has a 6-OH group (associated with more nausea). Fentanyl, propoxyphene, and methadone are completely different classes of opioids.

HOSAM ATEF,MDHOSAM ATEF,MD

Opioid pharmacology

Health & Medicine

opioid receptors narcotics

receptor nalbuphine

mu receptor antagonists

kappa receptor antagonist

activity naloxone

histamine muactivity

terminologyterminology

peripheral tissues mu