Pain and Opioid (narcotic) analgesics

1. PAIN AND OPIOID (NARCOTIC) ANALGESICS1
 DRUGS USED FOR TREATMENT OF PAIN
Pain is the most common symptom for which patients see a doctor. Optimal management of pain
requires that clinician should have a conceptual framework for what is happening to the patient in
mind and body. Different types of drugs are used for treatment of pain. In general, they include:
1. Drugs relieving pain due to multiple causes (analgesics):
 narcotic analgesics (morphine, fentanyl etc): act chiefly in the CNS
 non-narcotic analgesics (paracetamol, metamizole): act chiefly peripherally
2. Drugs relieving pain due to a single cause or specific pain syndrome only. They are
not classified as analgesics: e.g. naratriptan (migraine), carbamazepine (neuralgias), glyceryl
trinitrate (angina pectoris), adrenal steroids (inflammatory pain), butylscopolamine (spasm of
visceral smooth muscles), baclofen (spasm of striated muscles), etc.
3. Adjuvant drugs (anxyolitics, neuroleptics, antidepressants) may modify the perception of
pain and remove the concomitants of pain such as anxiety, fear, and depression. Placebo
gives relief in 3%.
4. Anaestethics are used during surgical operations, some diagnostic and other painful
procedures.
 FOUR MAJOR ASPECTS OF PAIN
1. Nociception is a consequence of tissue injury (trauma, inflammation) causing the release of
chemical mediators (ACh, PGE, NA, 5-HT, glutamate, bradykinin, endogenous opioids,
adenosine) which have neuronal or non-neuronal origin. These mediators activate nociceptors.
Nociceptors (pain receptors) transmit information by thin myelin (A-delta) and non myelin (C)
fibers to the spinal cord and brain.
2. Pain perception has a complex mechanism. It is a result of nociceptive impulses reaching
the brain (thalamus, cortex), plus impulses from other peripheral receptors, e.g. heat and
mechanoreceptors, whose threshold of response is reduced by the same chemical mediators.
These are processed in the brain whence modulated inhibitory impulses pass down to
regulate the continuing afferent input. But pain can occur without nociception (some
neuralgias). Pain is a psychological state; though most types of pain have a physical cause.
3. Suffering is a consequence of pain and lack of understanding by patients what the meaning
of pain is. Suffering comprises of anxiety, fear (particularly in acute pain) and depression (in
chronic pain), which will be affected by patient’s personality and his beliefs about the
significance of pain. Depression makes a major contribution to suffering. Pain threshold is
lowered by anxiety, anger, sadness, fatigue or insomnia.
4. Pain behavior comprises of nociception, pain perception and suffering. It includes facial
expression of patients, restlessness, seeking isolation or company, medicine-taking, etc. The
clinician’s task is to determine the significance of these items for each patient and according to
them to give suitable treatment. Analgesics may be needed, but not as a mainstay of therapy;
adjuvant drugs may be needed, as well as non drug therapy (surgery, radiation).
1
Adapted from P.N. Bennett and M. J. Brown (Clinical Pharmacology, 9th
Ed.Churchill Livingstone, London, 2003) by I.
Lambev.
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2. TYPES OF PAIN
1. Acute pain (defined as < 3 months duration) transmitted principally by fast conducting myelin
A-delta fibers. It has major nociceptive input (physical trauma, pleurisy, myocardial infarction,
perforated peptic ulcer). The narcotic and sometimes non-narcotic analgesics are used for
treatment of acute pain.
2. Chronic pain (defined as > 3 months duration) is transmitted principally by slow conducting
non myelin C fibers. It is better regarded as a syndrome rather than symptom. It is depressing
to the patient who sees no prospect for relieving the suffering. Analgesics alone are often
insufficient and adjuvant drugs as well as non drug therapy have increasing importance.
Chronic tumor pain is relieved by non-narcotic analgesics, narcotic analgesics and adjuvant
drugs (WHO). Continuous use of high efficacy opioids (e.g. morphine, pethidine) generally is
avoided in chronic pain. But the lower efficacy opioids (codeine, dextropropxyphene) may
often be used. Chronic pain syndrome especially after an attack of low back pain does not
respond to standard treatment with analgesics. In this case the use of antidepressants or
neuroleptics should be considered and also non drug therapy, including psychotherapy.
3. Neuropathic pain follows damage of the nervous system. Acute pain without nociceptive
(afferent) input (some neuralgias) is less susceptible to analgesics. The suitable drugs are
antidepressants and carbamazepine.
4. Transient pain is provoked by activation of nociceptors in skin and other tissues in absence
of tissue damage. It protects humans from physical damage coming from environment or
excessive stressing of tissue. It is a part of normal life and does not need treatment.
 HISTORY
Opium is the dried juice of seed head of poppy (Papaver
somniferum). It was used in prehistorical times (e.g. in Egypt,
Ebers’papirus – XVI b .n. c) as analgesic, tranquillizer,
antitussive drug and for treating of diarrhoea. The principal
active ingredient in crude opium – morphine, was isolated in
1806 from Frederic Sertürner, who tested pure drug on himself
and three young men. He observed that morphine caused
cerebral depression and relieved toothache. Gay Lussac
named this drug, which was the first discovered alkaloid, after
Morpheus (the son of Somnus) – morphine.
Opium contains two groups of alkaloids: with phenantrene
structure (morphine, codeine, thebaine) and with
isochinoline structure (papaverine, noscapine). Morphine
and codeine are narcotic analgesics; papaverine is a
vasodilatation; noscapine is antitussive agent which is
suspected of genotoxicity. Opium contains ≈10% morphine.
 RECEPTOR MECHANISMS OF OPIOID ANALGESIA
Endogenous opioid peptides (beta-endorphin, dynorphin, leu- and met-enkephalin) act as
neurotransmitters; they attach to specific opioid receptors, mainly μ, κ and δ, located at several
spinal and multiple supraspinal sites in the CNS. Beta-endorphin and dynorphine activate μ, κ
and δ-receptors; enkephalines activate μ and δ-receptors. Opioid receptors are part of the
family of G-protein-coupled receptors. Endogenous peptides and opioid analgesics inhibit
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3. adenylate cyclase and reduce intracellular cAMP. By these means, they promote open potassium
channels and prevent the opening of voltage-gated calcium channels which reduces neuronal
excitability and inhibits the release of pain neurotransmitter, including SP.
There two subtypes of μ-receptors – μ1 and μ2; μ1-receptor is responsible for analgesia at the
supraspinal level, and is also associated with euphoria and more than kappa-receptor with
psychical dependence, and μ2-receptor is associated with respiratory depression and inhibition of
gut motility; pupil contraction and sedation are principally μ-effects. The kappa receptor is
responsible for analgesia at the spinal level and is also associated with dysphoria, sedation and
less than μ1-receptor with physical dependence. Probably delta-receptor is associated with
analgesia in the periphery. There is also ORL1-receptor (opioid receptor like 1); nociceptin
activates this receptor and causes tolerance.
Pure opioid-agonist (e.g. codeine, ethorphine, heroin, morphine, pethidine) in general act on μ,
κ and δ-receptors. Methadone is a strong pure μ-agonist. Mixed partial agonist/antagonists are
buprenorphine, nalbuphine, pentazocine, etc; they have dual agonist/antagonist action on a single
receptor. This explains the different character of their effects. Loperamide and Racecadotril are
opiates that do not enter into the brain and, therefore, lacks analgesic activity. These drugs
stimulate mu- and delta-receptors, present on small and large intestine. Activation of mu-receptors
decreases peristaltic movements. Activation of delta-receptors contributes to their antisecretory
effects. Loperamide and Racecadotril are used to treat diarhoea. Naloxone and naltrexone are
pure μ/κ/δ-antagonist; nalorphine is μ-antagonist and partial κ-agonist.
 CLASSIFICATION OF OPIOID AGONISTS AND ANTAGONISTS
● Beta-endorphin: pure μ/κ/δ-agonist
● Dynorphine: pure μ/κ/δ-agonist
● Leu-enkephaline: pure μ/δ-agonist
● Met-enkephaline: pure μ/δ-agonist
OPIATE ANALGESICS (biosynthetic opioids)
● Alkaloids: Codeinе (weak μ/κ/δ-agonist), Morphinе (strong μ/κ/δ-agonist with t1/2 3 h; amp.
10 mg/1 ml), Papaverine
● Phytopreparations: Tinctura Opii (Laudanum), Tinctura anticholerica
OPIATE ANALOGUES (opioid analgesics, antitussives or opioid antagonists)
● Morphine derivatives: Heroin (diacethylmorphine: μ/κ/δ-agonist), Nalorphine (μ-
antagonist/partial κ-agonist), Naloxone (pure μ/κ/δ-antagonist)
● Codeine derivatives: Dextromethorphan (antitussive drug), Dihydrocodeine (DHC
Continus®
– tab. 60 и 90 mg), Oxycodone
● Thebaine derivatives: Buprenorphine (partial μ-agonist/κ-antagonist), Etorphine (pure
very strong μ/κ/δ-agonist)
• Cobinations with naloxone: Suboxone®
(buprenorphine и naloxone), Targin®
(oxycodone & naloxone)
SYNTHETIC OPIOID ANALGESICS
● Phenylpiperidines: Fentanyl (strong μ-agonist/δ-agonist), Pethidine (Meperidine –
modest μ/κ/δ-agonist)
● Methadones: Dextropopoxyphene (weak μ/κ/δ-agonist), Methadone (pure strong μ-
agonist with t1/2 35 h)
● Benzmorphans: Pentazocine (κ/δ-agonist/weak μ-antagonist)
● Heterogenic drugs: Afentanyl, Dextromoramide, Nalbuphine (partial κ-agonist/ δ-
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4. agonist/μ-antagonist), Sufentanil (strong μ-agonist/δ-agonist), Tilidine, Tramadol (partial
μ-agonist/inhibitor of NA reuptake/enhances 5-HT too)
COMPETITIVE OPIOID ANTAGONISTS (antidotes)
● Pure μ/κ/δ-antagonists: Naloxone, Naltrexone
● Partial: Nalorphine (Aethylmorphine®
– μ-antagonist/κ-agonist)
BIOSYNTHETIC AND SEMISYNTETIC OPIOIDS
▼MORPHINE is a pure and full opioid agonist. It acts on μ, κ, and δ-receptors. Its main
effects are:
On the CNS
 Depression, leading to analgesia,
respiratory depression, depression of
cough reflex, sleep).
 Excitation, leading to vomiting, miosis,
convulsions (very rare).
 Changes of mood (euphoria or
dysphoria).
 Tolerance and dependence
(psychological and physical).
Peripheral nervous system: Analgesia and
some anti-inflammatory effect.
Smooth muscle stimulation
 Gastrointestinal muscle spasm (with
constipation) and biliary tract spasm.
 Bronchospasm.
 Retentio urinae.
Cardiovascular system: Dilatation of
resistance and capacitance vessels.
Other effects: Sweating, histamine release,
pruritus, piloeraction, antidiuretic effect.
Morphine is the most useful high-efficacy opioid; it eliminates pain and also allows patients to
tolerate pain. It induces a state of relaxation, tranquility, detachment and well-being (euphoria), or
of unpleasantness (dysphoria), and causes sleepiness and lethargy. Morphine excites cats and
horses, though it is illegal to practical use. Analgesic, tranquillizing and hypnotic effects of
morphine are used in appropriate circumstances, e.g. acute pain and fear, as in myocardial
infarction or road traffic accidents.
Morphine depresses respiration, principally by reducing sensitivity of the respiratory centre to
increase in blood PaCO2. With therapeutic doses there is a reduced minute volume, but with
higher doses carbon dioxide narcosis may develop; in overdose the patient may present with
respiratory rate as low as 2/min. Morphine is dangerous when the respiratory drive is impaired by
disease (chronic obstructive lung disease, asthma, raised intracranial pressure after commotio
cerebri). In asthmatics, in addition to the depressive effect on the respiratory centre, morphine
may increase viscosity of bronchial secretion. Combination with alcohol (common with self-
poisoning) enhances respiratory depression.
Morphine also suppresses cough by central action. It stimulates the third nerve nucleus
causing miosis (pin-point pupils are characteristic of poisoning; at therapeutic doses the pupil is
merely smaller). The chemoreceptor trigger zone of the vomiting centre is stimulated, causing
nausea (in 10% of patients) and vomiting (15%). These effects of morphine are not only
unpleasant; they can be dangerous to patients soon after abdominal operation or cataract
surgery. A preparation of morphine plus antiemetics (atropine, etc) reduces this liability.
Some spinal cord reflexes are also stimulated, causing myoclonus; so morphine is unsuitable
for use in tetanus and convulsant poisoning; indeed, morphine can itself cause convulsions.
Morphine causes antidiuretic effect by releasing ADH, and this can be clinically important.
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5. Appetite is lost with chronic use. Morphine increases pressure in the sigmoid colon and colonic
diverticula may become obstructed and fail to drain into the colon. Pethidine neither produces
these high pressures nor prevents drainage, and so is preferable if the pain of acute diverticulitis
is severe enough to demand a narcotic analgesic. Morphine may also endanger anastomoses of
bowel immediately postoperatively and it should not be given in these cases.
Intrabiliary pressure may rise after morphine (as much after 10 times in 10 min), due to the
spasm of sphincter of Oddi. Sometimes biliary colic is worsened by morphine. In patients who
have had a cholecystectomy morphine can produce a syndrome sufficiently like an acute
myocardial infarction and this may cause diagnostic confusion; naloxone may give dramatic relief,
as may glyceryl trinitrate. Another unwanted result of this action of morphine is to dam back the
pancteatic juice and to cause a rise in the serum amylase concentration. Morphine is therefore
best avoided in pancreatitis.
Morphine is subject to extensive presystemic metabolism (mainly glucuroconjugation in gut
wall in liver) and its oral bioavilibity is only 20%. Given s.c. or i.m., it is rapidly absorbed if the
circulation is normal, but in circulatory shock absorption is delayed and it is best to inject
morphine very slowly i.v. Its t1/2 is 3 h and duration of analgesia is 3–6 h (shorter in younger than
in older patients). Usual dose of morphine is 10 mg s.c./i.m. Continuous pain suppression can be
achieved by morphine orally and s.c. 4-hourly. An average addict patient takes about 300 mg
morphine daily, which may be lethal for normal subjects. Some preparations of morphine sulfate
act 12 h and are administered two times daily. Morphine crosses the placenta and depresses
respiration of the fetus; it is also can cause fetal dependence.
Morphine and heroin dependence is more disabling physically and socially. Morphinism leads
to adaptive changes in the opioid receptor numbers, sensitivity and cellular response. The abrupt
withdrawal of morphine provokes rebound or withdrawal syndrome, which consist of opposite to
the normal action of opioids. Also, noradrenergic mechanism is modulated by endogenous
opioids, but these mechanisms are depressed by continuous opioid administration; withdrawal
syndrome can be described as “NA storm”. Opioid dependence is managed with methadone,
buprenorphine, clonidine, etc.
Principal uses of morphine and other opioids:
 Relief of moderate to severe acute pain (or chronic pain often in terminal illness)
 Brief relief of anxiety in serious and frightening diseases accompanied by pain (e.g. traumas
but without commotio)
 Relief of dyspnoe in acute left ventricular failure, and in terminal cases
 Premedication in surgery
 Treating of dry cough (usually codeine, dextromethorphan)
▼CODEINE (methylmorphine). It is a weak μ/κ/δ-agonist. About 10% is converted in morphine
(t1/2 3 h). It lacks efficacy for severe pain and most of its actions are about one-tenth those of
morphine. A qualitative difference from morphine is that large doses cause excitement.
Dependence occurs but much less than with morphine. Codeine is used for mild and moderate
pain and cough. About 10% of the population is resistant to the analgesic effect of codeine
because they lack the demethylating enzyme which converts it is to morphine. Codeine is
combined with paracetamol (e.g. Paracofdal®
, Paracodamol®
, Sedalgin neo®
).
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6. ▼Papaveretum (Omnopon®
) is a purified mixture of all opium alkaloids and it contains 50%
morphine.
▼
Dia
mp
rph
ine
(Heroin) is a strong μ/κ/δ-agonist, used in UK for acute pain, e.g. myocardiala infarction and
chronic pain (in palliative care). It provides a more rapid onset of pain relief than morphine
because it is more lipid soluble and enters the brain more rapidly. Its duration of action is the
same, but diamorphine may cause less nausea and hypotension than morphine. Diamorphine is
more soluble than morphine; this, together with its greater potency makes heroin suitable to
deliver by s.c. infusion through a syringe driver when continuous pain control is required in
palliative care. It is also used for severe cough.
▼Dextromethorphan is only used as antitussive drug which does not cause dependence.
▼Dihydrocodeine (DHC Continus®
– tab. 60 и 90 mg with duration 12 h) and Oxycodone are
opioids, suitable for mild and moderate pain; dihydrocodeine is used for symptomatic treatment of
cough too.
▼BUPRENORPHINE (partial μ-agonist/κ-antagonist) is a thebaine derivative. It is a mixed
agonist-antagonist and partial agonist (partial μ-agonist/κ-antagonist). It has less liability to induce
dependence and respiratory depression than pure agonists, little effect on cardiovascular system
and may spare the sphincter Oddi from induced spasm.
▼ETORPHINE (pure very strong μ/κ/δ-agonist) is also a thebaine derivative with remarkable
very high potency, more than 1000 times that a morphine. It is used to immobilize wild animals for
trapping and research purposes, since require dose, even for an elephant, is small enough to be
incorporated into a dart or pellet.
SYNTETIC OPIOIDS
▼PETHIDINE (Lydol®
– amp. 5% 2 ml; meperidine) is a modest μ/κ/δ-agonist. It is effective for
moderate and severe pain, but its duration is 2–3 h (shorter than morphine). Pethidine does not
suppress cough; it is less likely to constipate (but can induce contraction of sphincter of Oddi
similar to morphine); it causes retentio urinae less than morphine and do not prolong childbirth; it
has a little hypnotic effect.
▼FENTANYL and SUFENTANIL are highly potent phenylpiperidine derivatives (strong μ-
agonist/δ-agonist), with actions similar to morphine, but short lasting, particularly sufentanil. Their
main use in anaesthesia, and they may be given intrathecally. They also used in patient-
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7. controlled infusion systems, where a short duration of effect is advantageous. Fentanyl (amp. 0,1
mg/2 ml i.m.) is usually combined with droperidol (amp. 5 mg/2 ml i.m.) to cause neuroleptic
analgesia (e.g. in acute myocardial infarction).
▼TRAMADOL (t1/2 6 h) is a relatively weak μ-agonist and neuronal NA uptake inhibitor; it also
enhances 5-HT release. It is rapidly absorbed from GIT and only 20% of an oral dose undergoes
first-pass metabolism. Tramadol is approximately as effective as pethidine for postoperative pain
and as morphine for moderate chronic (including tumour) pain. Tramadol is claimed to be less
likely to constipate, depress respiration and addict. Confusion, convulsions, hallucinations, and
anaphylaxis have been reported with its use.
▼PENTAZOCINE is a mixed agonist/antagonist (κ/δ-agonist/weak μ-antagonist). It has one-third
of the analgesic potency of morphine. At high doses pentazocine causes only slight respiratory
depression, and it causes marked dysphoria, with nightmares and hallucinations, rather than
euphoria. It also tends to rise, rather than lower arterial blood pressure.
▼DEXTROPROPOXYPHENE (t1/2 5 h) is structurally similar to methadone and differs in that it is
less analgesic and less dependence producing. It is weak μ/κ/δ-agonist analgesics usefulness
approximates to that of codeine, but its duration of action is longer. Dextropropoxyphene is
combined with paracetamol. It interacts with warfarin, enhancing its anticoagulant effect.
▼METHADONE is a pure strong μ-agonist. It is a drug of first choice for treatment of opioid
dependence; it has a long t1/2 (35 h) and attenuates withdrawal syndrome. The initial dose of
methadone is 10–20 mg daily. One course of treatment is 7–21 days. All process takes many
months and includes more gradually decreases as the dose is lowered. Methadone is the
preferred drug in opioid maintenance programs for addicts who tend to withdraw.
 CLASSIFICATION OF OPIOIDS BY ANALGESIC EFFICASY
Low efficacy for mild and
moderate pain
High efficacy for severe pain
codeine, dihydrocodeine,
dextripropoxiphene, nalbuphine,
oxycodone, pentazocine
alfentanil, buprenorphine, dextromoramide, diamorphine
(heroin), fentanyl, methadone, morphine, papaveretum
(Omnopon®
) pethidine (meperidine, Lydol®
), sufentanil,
tramadol
OPIOID AGONISTS WHICH DOES NOT CROSS BBB
• Loperamide (Imodium®
)
• Racecadotril (Hidrasec®
)
These drugs stimulate mu- and delta-receptors, present in the small and large intestines. Activation
of mu-receptors decreases peristaltic movements. Activation of delta-receptors contributes to their
antisecretory effects. Although all opioids such as morphine and codeine have antidiarrhoeal
effects, their CNS effects and dependence liability limit their usefulness. Loperamide directly
stimulates mu- and delta-receptors. Racecadotril blocks enzyme encephalinase and increases
local concentration of enkephalins in intestinal mucosa which then stimulate mu- and delta-
receptors. This drug can be used orally from children under 5 years old (including babies), but
Loperamide is contraindicated in children < 5 years old.
OPIOID ANTAGONISTS
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8. ▼NALOXONE (t1/2 75 min) is a pure (full) competitive antagonist at μ, κ and δ-receptors; it has
no agonist activity. Naloxine antagonizes both full agonist and partial agonist opioids. It induces
an acute withdrawal syndrome in opioid-dependent subjects. Naloxone undergoes high
presystemic elimination when swallowed and is not used by this route. Given i.v., it caused
reversal of opioid-induced respiratory depression in 1–2 min; reversal of analgesia and depressed
consciousness can be slower. The effect of naloxone is 10 min and it should be given by i.v.
boluses injection of 100 mcg at 2-min intervals until changes in respiration, pupils or
consciousness indicate response; the subsequent doses may be given by i.m. injection. A
continuous i.v. infusion commencing with 2.5 mcg/kg/h may be required for days with opioids
having a long t1/2 (e.g. methadone). Naloxone is also used to counter excess opioid effects after
surgical analgesia or childbirth.
▼NALTREXONE (t1/2 4 h: active metabolite 13 h) is similar to naloxone but longer-acting, with
duration of effect 1–3 days according to dose. It can be used orally to assist in rehabilitation of ex-
opioid abusers who are fully withdrawn.
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