1. Tripoli University
Faculty of Pharmacy
Drug Treatment of Pain
2011-2012
BY
PROF. ABDALLA SALEM ELHWUEGI (Ph.D.)

2. Receptor Effector Mechanisms
Receptors coupled to GTP-binding proteins
1. Postsynaptic agonist effects produce increased K+
efflux leading to hyperpolarization and reduction in
the firing rate blocking pain transmission
2. Presynaptic agonist actions decrease voltage-gated
Ca++ influx and reducing excitatory neurotransmitter
release.
3. Inhibition of adenylyl cyclase activity decreases
intracellular calcium thus reducing neurotransmitters
release.

3. Properties of Opioid Agonists
1. Bind with high affinity to opioid receptors.
2. Binding reversed by narcotic antagonists.
3. Cross-tolerance exhibited to narcotic agonist
administration.
4. Dependence is produced with chronic
administration.
5. Withdrawal reaction induced by the administration
of narcotic antagonist in dependent animals.

4. Pharmacokinetics
A) absorption
1. Depending on the agent, oral absorption is usually poor
and variable due to first pass metabolism and
glucuronidation (the bioavailability of morphine is only
25%)
2. Absorption following IM administration is usually
complete with maximum blood levels is 15-30 min

5. Pharmacokinetics
B) Distribution
1. Distribution to tissues is based largely on blood flow.
2. CNS levels based on:
• Blood-brain barrier.
• Lipid solubility.
• Protein binding.
• Rapid conjugation with glucuronic acid.

6. Pharmacokinetics
C) Metabolism
1. Rapid conjugation with glucuronic acid
2. Esters such as meperidine are hydrolyzed by esterases
3. Morphine-6-glucuronide is an active metabolite
4. Accumulation of the n-demethylation product of
meperidine (normeperidine) can produce seizures
D) Elimination
1. Water soluble metabolites eliminated by renal mechanisms
2. Glucuronide conjugates are eliminated in bile.

7. Pharmacological Actions
I) Central nervous system effects
1. Analgesia
A. Inhibit nociception primarily by interacting with mu1 receptors
•Raise the threshold for pain perception.
•Diminish the reaction to the pain (even though pain is perceived)
B. Continuous dull pain is relieved more effectively than sharp,
intermittent pain.
C. Pain relieving is usually accompanied by euphoria.

8. Pharmacological Actions
2. Respiratory depression
All narcotic analgesics produce dose-dependent
respiratory depression
• Decreased sensitivity of the respiratory center
chemoreceptors to CO2
• Direct effects to decrease respiratory rhythmicity,
• Decrease in rate, minute volume and tidal
exchange.

9. Pharmacological Actions
3. Sedation
A. Drowsiness and sedation produced by the narcotic analgesics is
quite variable based on age, debilitation, other drugs.
B. Decreased anxiety may also be a component.
4. Mood changes
A. Patient response varies, first dose may produce unpleasant
experience (dysphoria) if the agent is given in the absence of
pain.
B. Euphoria or a feeling of being “detached” (pleasant floating
sensation with a relaxed, dreamy state) after repeated
administration (reason for abuse).

10. Pharmacological Actions
5. Separate central effects
A. Miosis occurs as a result of increased activity in the
parasympathetic nerve innervating the pupil
B. Nausea/vomiting occurs as a result of direct stimulation of the
chemoreceptor trigger zone for emesis, in the area postrema of
the medulla. All clinically useful mu agonists produce some
degree of nausea and vomiting.
C. Cough suppression is a useful effect (antitussive) and results
from direct depression of the cough center in the medulla.
D. Truncal rigidity occurs as a result of increased tone in large
trunk muscles probably due to increased impulse activity from
supraspinal sites.

11. Pharmacological Actions
II) Peripheral effects
1. Minimal effects on the cardiovascular system (blood
pressure, cardiac rate and rhythm) in the supine patient.
Morphine does produce arteriolar and venous dilation and
may produce orthostatic hypotension (see histamine release
effects).
2. Histamine release (especially with morphine) can produce
cutaneous flushing and loss of body heat (hypothermia).
Although the effects vary according to different opiates,
bronchoconstriction and hypotension may occur.

12. Pharmacological Actions
3. Constipation due to decreased propulsive contractility
(peristalsis) in the small and large intestine.
4. Biliary colic due to constriction of biliary smooth muscle
and the sphincter of Oddi in the biliary tract.
5. Urinary retention due to increase tone in the ureter,
detrusor muscle of the urinary bladder and vesicle
sphincter.

13. Tolerance and Physical Dependence Tolerance
1) tolerance
A. With repeated administration, fast & strong tolerance to the
effects of morphine and other opiates can develop over a
period of 1-3 weeks. Tolerance can be as great as 35 fold the
initial dose.
B. Tolerance is gained to all agonist effects except miotic and
constipating effects.
C. Cross tolerance to all agonists occurs and includes tolerance to
analgesic, euphoric, sedative and respiratory depressant
effects.
D. Less tolerance is gained to the agonist/antagonist drugs and
also tolerance to methadone develops more slowly and to a
lesser degree. Tolerance is gained.

14. Tolerance and Physical Dependence Tolerance
2) Dependence
A. Physical dependence parallels the development of
tolerance.
B. Without the continued presence of agonist at the receptor
site, the cellular processes linked to the receptor become
hyperexcitable, leading to characteristic withdrawal or
abstinence syndrome
C. Withdrawal can be precipitated in a dependent individual
by administering a narcotic antagonist.

15. 3) Withdrawal Syndroms
A. Are not fetal but are not pleasant.
B. The followings are the signs & symptoms.
SYMPTOMS SIGNS
Regular Withdrawal
Craving for opioids Pupillary dilation
Restlessness, irritability Sweating
Increased sensitivity to pain Piloerection ("gooseflesh")
Nausea, cramps Tachycardia
Muscle aches Vomiting, diarrhea
Dysphoric mood Increased blood pressure
Insomnia, anxiety Yawning and Fever
Protracted Withdrawal
Anxiety Cyclic changes in weight, pupil size, respiratory
Insomnia center sensitivity
Drug craving

16. Treatment of opioid withdrawal & physical dependence
Opioid withdrawal & physical dependence signs and symptoms can
be treated by three different approaches:
1. Change the patient from a short-acting opioid such as heroin
to a long-acting one such as methadone. A 20% per day dose
reductions during the course of detoxification is applied.
2. A second approach to detoxification involves the use of
clonidine or lofexidine which blocks autonomic hyperactivity.
Clonidine, acting via distinct receptors but by cellular
mechanisms that mimic opioid effects, can alleviate many of
the symptoms of opioid withdrawal. However, clonidine does
not alleviate generalized aches and opioid craving
characteristic of opioid withdrawal.

17. Treatment of opioid withdrawal & physical dependence
3. Naltrexone (opioid antagonist) treatment can be
utilized after detoxification for patients with high
motivation to remain opioid free. It will also acts
to restore normal opioid receptors sensitivity.
4. New treatment options. Buprenorphine is a mu
opioid partial agonist, it has minimal withdrawal
symptoms, low potential for overdose, long
duration of action, and ability to block heroin
effects comparable to that of naltrexone.

18. Interactions with Opioids
I) Disease states/injury
A. Presence of pulmonary disease or hepatic
dysfunction are major considerations.
B. Contraindication for narcotic analgesics in
head injury without assisted ventilation.
C. Patients with pancreatitis may
experience a further increase in biliary tract
pressure with narcotic analgesics

19. Interactions with Opioids
II) Drugs
1. Combined administration of narcotic analgesics
and CNS depressants (barbiturates, antianxiety
agents, antipsychotics) result in potentiation of the
sedative effects.
2. Meperidine (and possibly other narcotic
analgesics) administered to patients taking MAO
inhibitors can produce excitation, convulsions,
hyperpyrexia, respiratory depression and
hypotension.

20. Opioids overdose toxicity
A. “Triad”
1. Depressed respiration
2. Pinpoint pupils (except with meperidine)
3. Coma.
B. Treatment
1. First step in treatment is to establish an airway for
ventilatory support
2. Judicious administration of a narcotic antagonist.

21. Narcotic Antagonists
1) Full antagonist
binds to the mu, kappa and delta opiate receptors (affinity), but
has no action or effect on the receptor (efficacy=zero).
A. Naloxone antagonizes the actions of narcotic analgesic
agonists. Half-life of 1-2 hrs following IV administration.
B. Nalmefene has a longer half-life (8 hrs) and thus provides
better matching of kinetics of longer half-life agonists.
C. Naltrexone is also a pure antagonist which is much longer
acting than naloxone and can be given orally.

22. Narcotic Antagonists
2) Agonist - antagonist
binds to mu, kappa or delta receptors, but also has partial agonist
effects at kappa or delta receptors
A. Nalorphine has antagonist actions at mu receptors
B. Pentazocine has weak antagonist actions at mu receptors and
moderate agonist actions at kappa receptors
C. Butorphanol is similar to pentazocine but more potent as an
agonist at kappa receptors
D. Buprenorphine functions as an agonist-antagonist in the
presence of morphine (greater affinity for mu receptor), but as
a selective “partial” agonist since does not interact with kappa
and delta receptors.

23. Narcotic Antagonists
Uses of full antagonists
1. Intravenously to reverse excessive respiratory and CNS
depression due to narcotic analgesic administration (naloxone,
nalmefene)
2. Orally to decrease craving and maintain opiate-free state in
opiate-abusing patients (naltrexone)
Precautions
1. Reversal of the beneficial effects of the agonist when attempting
to reverse the deleterious effects (respiratory depression).
2. Antagonist may have a shorter half-life compared to morphine
and respiratory depression will reoccur.
3. Precipitation of withdrawal in physically dependent individuals

24. Clinical Uses of Opioids
Opioid analgesics provide symptomatic relief of pain, cough,
or diarrhea, but generally the underlying disease remains.
I) Pain.
For many types of pain, aspirin should be tried first. If
relief of pain is insufficient, these drugs then can be
combined with orally effective morphine-like agents,
such as codeine, or with agonist/antagonist opioids.
Combinations of these two classes of drugs usually
can achieve an analgesic effect with fewer side
effects.

25. Clinical Uses of Opioids
Morphine (10 mg/70 kg) given either subcutaneously or
intramuscularly is sufficient to relieve moderate-to-severe
pain in 70% of patients. Intravenous administration may
be indicated for severe pain, using either continuous
infusion or intermittent dosing. Morphine is available
orally in standard tablets and controlled-release
preparations. Codeine is widely used orally due to its
high oral/parenteral potency ratio. Orally, codeine at 30
mg is approximately equianalgesic to 325 to 600 mg of
aspirin. Combinations of codeine with aspirin or
paracetamol usually provide additive actions, and at
these doses analgesic efficacy can exceed that of 60 mg
of codeine.

26. Clinical Uses of Opioids
Pain of terminal illness and cancer pain.
The management of chronic pain associated with
malignant disease or terminal illness recommend that
opioids be administered at sufficiently short, fixed
intervals so that pain is continually under control.
Postoperative pain.
Oral codeine or oxycodone combined with nonsteroidal
antiinflammatory agents often provides adequate
analgesia for mild pain. When pain is more severe,
opioid analgesics are used in the immediate
postoperative period.

27. Clinical Uses of Opioids
Obstetrical analgesia
The use of morphine-like drugs in obstetrical analgesia is a
highly specialized field requiring experience and sound
judgment to ensure effective analgesia, safety for the
fetus, and minimal interference with the progress of
labor.

28. Clinical Uses of Opioids
2) Cough.
Cough suppression (antitussive) often occurs with lower
doses than those needed for analgesia.
A 10- or 20-mg oral dose of codeine, although ineffective
for analgesia, produces a demonstrable antitussive
effect, and higher doses of codeine produce even more
suppression of chronic cough.
Noscapine is a naturally occurring opium alkaloid of the
benzylisoquinoline group; except for its antitussive
effect, it has no significant actions on the CNS in doses
within the therapeutic range. The drug is a potent
releaser of histamine, and large doses cause
bronchoconstriction and transient hypotension.

29. Clinical Uses of Opioids
Dextromethorphan is the d isomer of the codeine analog
levorphanol; however, unlike the l isomer, it has no
analgesic or addictive properties and does not act
through opioid receptors. In therapeutic dosages, the
drug does not inhibit ciliary activity, and its antitussive
effects persist for 5 to 6 hours. Its toxicity is low, but
extremely high doses may produce CNS depression.
Levopropoxyphene napsylate, the l-isomer of
dextropropoxyphene, in doses of 50 to 100 mg orally,
appears to suppress cough to about the same degree as
does 30 mg of dextromethorphan. Unlike
dextropropoxyphene, levopropoxyphene has little or no
analgesic activity.

30. Clinical Uses of Opioids
3) Dyspnea.
Intravenous morphine is used to alleviate the dyspnea of
acute left ventricular failure and pulmonary edema. The
mechanism underlying this relief may involve an
alteration of the patient's reaction to impaired
respiratory function and improvement of cardiac output
through a decreased of peripheral resistance and an
increased capacity of the peripheral and splanchnic
vascular compartments .

31. Clinical Uses of Opioids
4) Antidiarrheal effect
The morphine-like opioids are effective in
treating diarrhea after ileostomy or colostomy,
and in treating exhausting diarrhea and
dysenteries due to a number of causes.
Synthetic opioids such as diphenoxylate,
loperamide, and difenoxin, are used
exclusively for this purpose as they have no
CNS effects.

32. Clinical Uses of Opioids
5) Special Anesthesia
High doses of morphine or other opioids have
been used as the primary anesthetic agents
in certain surgical procedures. Although
respiration is so depressed that physical
assistance is required, patients can retain
consciousness.