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CLINICAL PHARMACOKINETICS OF THE OPIOIDS USE IN TERMINAL PAIN

1. Pharmacological Overview:

(a) Mode of action:

- Bind to opioid receptors distributed throughout CNS ® altered modulation of pain impulses.

(b) Uses:

- Acute pain, eg AMI, post-surgery.

- Chronic pain: Cancer.

(c) Desirable features:

- Effective analgesics.

- Alter mood 

- Relief of anxiety.
- Sense of well-being.

(d) Undesirable features:

- Variable dosage requirements.

- Poor oral bioavailability.

- Short half-lives.

- Side effects:-

- Sedation, dizziness.
- Nausea, vomiting.
- Constipation.
- Biliary spasm.
- Respiratory depression.

Chronic administration:

- Tolerance.

- Physical dependence. 

- Addiction.

(e) Pharmacological differences:

Opioids
Pure Agonist	Mixed Agonist - Antagonist	Antagonist
Morphine, Pethidine, etc	Pentazocine, Buprenorphine	Naloxone = Narcan
	Advantages
	Sedation, respiratory depression.  dependence and abuse potential.
	Disadvantages
	“Ceiling effect”.  Withdrawal symptoms if previously on agonist.  Psychotic side effects.

(f) Equianalgesic doses (mg):

Agonist	Parenteral	Oral	Duration of Analgesia (hr)
Morphine	10	60	4
Heroin	4	30	3-4
Methadone	10	20	6-24
Pethidine	100	300	3
Fentanyl	0.1	--	1
Dextromoramide	7.5	10	2
Oxycodone	10	30 (rectal)	8
Codeine	30	90	4
Dihydrocodeine	15	45	4
Dextropropoxyphene	--	200	8
Agonist/Antagonist
Pentazocine	60	180 (weak analgesic)	3
Buprenorphine	0.3	0.8 (s.l.)	7

2. Pharmacokinetic Overview:

(a) Absorption:

Extent of oral absorption is dependent on hepatic extraction (first-pass effect).

Eg:-

 

Drug	Hepatic Clearance	Oral Bioavailability
Fentanyl  Morphine  Pentazocine  Burprenorphine	High	~ 20-40% (variable)
Codeine  Pethidine  Alfentamil	Intermediate	~ 50%
Methadone	Low	~ 90%

(b) Distribution:

- Opioids display “multi-compartmental” distribution behaviour: Re-distribution occurs firstly into muscle, and then into poorly perfused tissues (eg. fat).

- High apparent volumes of distribution.

- Care with repeated dosing of “short acting” opioids, eg. Fentamyl: Accumulation in body and saturation of tissue binding - prolonged effects.

- Generally low plasma protein binding (µ1 - acid glycoprotein).

Eg. Morphine 20-30%
      Methadone 60-90%

(c) Elimination:

- Opioids undergo extensive metabolism.

- Metabolites may be active/toxic, eg. Heroin, Codeine, Pethidine.

- Renal excretion is a minor route of elimination, but may be very important in the excretion of active metabolites, eg. Pethidine, Morphine.

- There is considerable inter-patient variability in the metabolism of opioids.

- Rate of elimination governs dosage interval, eg. Morphine Vs Methadone.

- elimination in chronic liver disease (and pharmacodynamic sensitivity).

TABLE: Comparison of Some Properties of Clinically Important Opioid Drugs
Opioid Drug	Intravenous Dose (mg)¶	Partition Coefficient§	Total Body Clearance¤ (L/min)	Half-life (Hours)¤	Apparent Volume of Distribution (L)¤
Morphine	10	1	0.8-1.2	1-4	200
Pethidine	100	21	0.4-0.8	2-7	250
Fentanyl	0.1	950	0.8-1.3	2-7	400
Methadone	10	115	0.1-0.2	25-45	400
Alfentanil	0.5	130	0.2-0.6	1-3	40
Sufentanil	0.02	1750	0.5-1.0	2-5	100
Pentazocine	30	NA	0.8-1.2	2-5	400
Buprenorphine	0.3	NA	1.0-1.5	2-5	200
Nalbuphine	12	NA	0.8-1.4	3-7	500
Butorphanol	0.2	NA	2-4	2-4	500
¶ Human analgesic doses (approximate).  § Octanol:pH 7.4 buffer (approximate)/  ¤ Typically reported ranges.  NA = Not available

 

3. Plasma Level Monitoring of Opioids:

With the opioids, the relationship between plasma concentrations and pharmacological response is not clear-cut because the response is not clearly defined.

Many anatomical, physiological, and psychological factors can modify the analgesic response, and produce large inter-individual and intra-individual variations in the response to opioids:-

Eg: 

- Cause of the pain and extent of tissue damaging.
- Individual pain threshold.
- Previous exposure to opioids and tolerance.
- Clinical contribution of active metabolites.
- Surroundings, and care that is offered by medical and nursing staff.

 

4. Clinical Applications:

(a) Acute pain:

(i) Repeated im administration:

Eg. 

Morphine 5-10mg - 3-4 hourly.
Pethidine 50-100mg - 3-4 hourly.
Methadone 10mg - 6-8 hourly.

- Inter-patient variability.
- Rapid clearance.

(ii) Continuous IV infusion:

Eg. 

Morphine 10mg over 30 mins; 2.5-5.0mg/hr.
Pethidine 100mg over 30 mins; 25-37.5mg/hr.

(iii) Demand analgesia:

Patient controls administration rate.

(iv) Intermittent Methadone dosing:

- Half-life 10-80 hours.

- Eg. 

20mg IV every 12-24 hours.

(b) Chronic pain (terminal illness):

(i) Oral opiates:

Alternative Opioids:

Methadone: 8 hourly or prn.
Pethidine: Short action toxic metabolite.
Dextromoramide: Short action.

Side Effects:

- Drowsiness - tolerance develops.
- Constipation - Prophylactic laxative, eg. Coloxyl.
- Nausea - 10% patients.

(ii) Parenteral administration:

- Im injections.

- Continuous IV infusion or SC infusion.

- Epidural opioids:-

- More selective analgesia.
- Risk of delayed respiratory depression.

(iii) Rectal administration:

- Oxycodone 15-60mg 8 hourly.

- Convenience.

- Nocturnal pain.

- Disadvantage - delayed absorption.

 

5. Summary: Use of Analgesics in Terminal Illness:

(a) Individualised treatment.

(b) Know the potency duration of action, and side effects of available analgesics.

(c) Morphine is the opioid analgesic of choice for severe chronic pain.

(d) Administer analgesics on a fixed-time basis (exception: Methadone).

(e) Opioid plus non-opioid often effective.

(f) Tolerance to opioid analgesic: Consider change to another opioid.

(g) Addiction irrelevant.

 

1. Oral Absorption:

- Rapid: Peak levels within 30-90 minutes.

- Extent of absorption approx. 40% due to significant first-pass metabolism.

 

2. Distribution:

- Large and variable Vd: Approx. 4L/kg (1-6L.kg).

- Readily distributed throughout the body to highly perfused tissues, eg. lungs, kidney and liver.

- Binds to albumin and gamma-globulin (20-40% bound in plasma).

 

3. Elimination:

- Principally eliminated by metabolism in the liver.

- Main metabolites: 

Morphine-3-glucuronide (> 50%).
Morphine-6-glucuronide (approx. 5%) - active.

In cancer patients receiving oral Morphine, steady-state plasma levels of M3G are approx. 20-fold, and M6G approx. 3-fold, higher than the Morphine concentrations.

Pain relief has been reported for up to 7 hours after intravenous administration of M6G (1mg/70kh body weight).

Most of the analgesic effect with chronic Morphine therapy may be due to M6G, rather than due to Morphine itself.

M6G accumulates in patients with renal impairment: Morphine dosage requirements are generally reduced in these patients.

Approximate Equianalgesic Dosages (mg)
Drug	Parenteral	Oral	Duration of Analgesia (hr)
Morphine	10	60 (single dosing) 30 (chronic dosing)	4-5
Pethidine	100	300	2-4
Heroin	5	30	3-4
Methadone	10	20	8-12
Dextromoramide	7.5	10	2-3
Oxycodone	15	30 (pr)	4 (po), 8 (pr)
Fentanyl	0.1	--	0.5-1
Codeine	120	240	4-6
Dihydrocodeine	15	45	4-6
Dextropropoxyphene	--	200	4-8
Pentazocine	60	180	3-6
Buprenorphine	0.3	0.8 (sl)	7-8
Aspirin	--	1800	4-6

 

Morphine:

- The standard strong opioid for cancer pain.

- Use the simples route (oral) and the simplest formulation (mixture).

- Produces analgesia lasting 3 to 5 hours; administer every 4 hours “by the clock” and never give as required on a prn basis (except additional doses).