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Opioid Analgesics

T. Binder Department of Pharmacology

Drugs which relieve pain without causing unconsciousness. Opioids NSAIDs

Definition: Unpleasant sensory and emotional experience associated with actual or potential tissue damage. The perception of noxious stimuli is termed nociception. Opioids can change both the sensation and the affective response.

The sensation of pain arises from the activation of the peripheral terminals of C-fibres and Adfibres in response to mechanical and thermal stimuli. At their central terminals in the spinal cord C-fibres release peptides such as Substance P which activate spinal cord neurones.

Endogenous Opioids
Derived from 3 precursor molecules: Proopiomelanocortin [POMC], pro-enkephalin and pro-dynorphan

Dynorphin (, ) - endorphin (, ) Enkephalin (, )


Endogenous Opioids
Analgesia Motivation and reward Feeding Locomotor activity Thermoregulation Stress and anxiety

Receptor classes
Mu () - analgesia, respiration, cardio, intestinal transit, feeding, mood, thermoregulation, hormone secretion and immune function Kappa () - analgesia, diuresis, feeding, hormone secretion, immune function. Delta () - analgesia, mood, cardioregulation, immune function.

Cellular actions
Inhibit adenylate cyclase thereby reducing intracellular cAMP Facilitate the opening of K+ channels Inhibit the opening of Ca2+ channels

Opioid induced analgesia


Excitability and Neurotransmission



Oxycodone Tramadol

Morphine Pethidine Methadone Buprenorphine Fentanyl


Well absorbed orally Metabolised in liver to morphine and codeine-6 glucoronide, excreted in urine Indication: mild to moderate pain, diarrhoea, cough half life: 4 - 6 hrs


10 x potency of codeine Indication: mild to moderate pain, antitussive Half life: 2-3 hrs


Bioavailability 25% Metabolised in liver to M3G and M6G, excreted in urine Indication: Moderate and severe pain, cancer-related pain, post operative pain. Half life: 2 - 4 hrs


Pethidine [Mepiridine]
1/10 potency of morphine Bioavilability 40 to 60% Metabolised in liver to norpethidine, excreted in urine. Indications: moderate to severe pain. Half life: 3 - 4 hrs Not recommended for long term use

Bioavailability > 85% Metabolised in liver, mainly excreted in urine Indication: moderate to severe pain, opioid maintenance programs (decreases rapid lows and highs seen with heroin) Half life: 13 - 58 hrs

Bioavailability 16% Metabolised in liver, excreted in bile and urine Indication: moderate pain Partial agonist; may be used for opioid withdrawal or maintenance Half life: 6 - 9 hrs

50 100 X potency of morphine Metabolised in liver, excreted in urine Indication: moderate to severe pain, child birth, anaesthetic/analgesic Half life: 1hr (high lipid solubility)

Low affinity for opioid receptors Non-opioid actions; inhibits noradrenaline and serotonin reuptake Indication: moderate to severe pain including post-operative pain and neuropathic pain Half life: 5 hrs

Which opioid?
Consider: Severity and duration of pain Previous experience with opioids Co-morbidity Age Biological variability in response Pharmacological e.g. potency, half-life, active or toxic metabolites Available formulations

Opioid therapy in drug dependant individuals

Under treatment serious problem / challenge Assessment: past and present drug use; quantity and frequency Tolerant individuals require higher starting doses and often demonstrate a shorter duration of action Dose titration according to patient response Drug free [abstinent patients] may be reluctant to accept therapy

Patients maintained on Methadone

Methadone can be used to treat pain Dosing frequency should be increased Dose must be titrated to patient response; patients typically require higher doses. Patient can remain in maintenance program; requires good communication.


Patients maintained on buprenorphine

Buprenorphine is a partial agonist with high affinity for -opioid receptors May act as a competitive antagonist of full agonists Treatment strategies:
Use of non-opioid analgesics; NSAIDs Higher doses of a full agonist may overcome buprenorphine antagonism [dose should be titrated] Transfer patient to a full agonist


Route of administration
Use the least invasive route possible

Oral; least invasive; consider bioavailability, slow absorption Intramuscular; injections painful, absorption may be erratic, not recommended Subcutaneous; less painful than i.m., similar onset of pain relief Intravenous; rapid onset
Steady state concentrations approached in 4 half-lives unless loading dose is used

On demand - a) on recurrence of pain - b) fixed intervals Patient controlled Analgesia (PCA) infusion systems -pre determined: intermittent injection dose, lockout interval, drug over time limits

Pain Control
Morphine 10 mg oral, s.c. or i.m. will control pain in 70% of patients with mild - moderate pain. Severe pain may require i.v. morphine via intermittent or continuous infusion. May also use PCA.

Factors that affect pain

Pain Sensation Reporting
Home environment Patient beliefs coping skills cultural background concept of suffering gender placebo effect Biological variability; genetics


Opioid Side Effects

Miosis Sedation and euphoria (or dysphoria) Respiratory depression; CNS depression Suppression of the cough reflex Emesis: Nausea and vomiting Constipation

Respiratory depression
Opioids decrease the sensitivity of chemoreceptors to CO2 Usually little respiratory decline at therapeutic doses Can be assessed by the degree of sedation Caution:
Patients with decreased respiratory reserve; e.g. chronic airway limitation, morbid obesity Head trauma; increased CO2 tension in blood and cerebrospinal fluid increased intracranial pressure


Management of adverse effects

Treating symptoms
Laxatives; anti-mimetics

Reducing the dose Opioid rotation Naloxone [respiratory depression]


Tolerance and dependence

Tolerance - increasing dose to produce the same effect. Physical dependence - withdrawal when opioid removed. -Chills, fever, sweating, vomiting, diarrhoea, nausea, anxiety Psychological dependence compulsive use of drug to relieve anxiety.


Acute Toxicity
Opioid overdose leads to coma with hypotension and marked respiratory depression, may be fatal.
Addiction; multiple drug use; drug purity


Antagonists: Naloxone and Naltrexone

Major clinical use is the management of acute opioid overdose. Reverses CNS and respiratory depression Acts on all 3 receptors but highest affinity for Naloxone: short half life compared to agonists. Specific antagonists: CTOP; norBNI; naltrindole

Factors affecting opioid kinetics

Disease Hepatic impairment renal impairment [accumulation of metabolites; codeine, morphine, pethidine] Drug interactions Additive CNS depression (ethanol, sedatives, anesthetics, anti-histamines, MAO inhibitors) Age: neonates and elderly Genetics: CYP 2D6; CYP 3A4


Opioid insensitive pain

Opioids are not equally effective for all pain types May lead to toxicity before adequate pain control is achieved Common types
Bone pain [metastases] Neuropathic pain Nerve compression