Analgesics angina pectoris by mikesanye

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									                               Medical University of Sofia, Faculty of Medicine
                               Department of Pharmacology and Toxicology
                               2, Zdrave Street, 1431 Sofia, BULGARIA Phone/Fax (+359 2) 9172-621 or 625



                            PAIN AND OPIOID (NARCOTIC) ANALGESICS1
                             Assoc. Prof. Ivan Lambev, MD, PhD (itlambev@mail.bg)

 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):
         narcotics 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).

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.

     1   Adapted from P.N. Bennett and M. J. Brown. Clinical Pharmacology, 9th Ed.Churchill Livingstone, London, 2003.
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 analgesic; 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 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; which explains the different character of its effects. Loperamide is an opiate that does
not enter the brain and, therefore, lacks analgesic activity. Like other opiates it inhibits peristalsis, and it is 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
ENDOGEOUS OPIOID PEPTIDES
● 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)
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-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. The main effects of morphine are:




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On the CNS                                                                  Smooth muscle stimulation
 Depression, leading to analgesia, respiratory                              Gastrointestinal muscle spasm (with constipation)
     depression, depression of cough reflex, sleep).                             and biliary tract spasm.
 Excitation, leading to vomiting, miosis, convulsions                       Bronchospasm.
     (very rare).                                                            Retentio urinae.
 Changes of mood (euphoria or dysphoria).                                  Cardiovascular system: Dilatation of resistance and
 Tolerance and dependence (psychological and                               capacitance vessels.
     physical).                                                             Other effects: Sweating, histamine release, pruritus,
Peripheral nervous system: Analgesia and some anti-                         piloeraction, antidiuretic effect.
inflammatory 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 if 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, acting by releasing
ADH, and this can be clinically important. 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:                               Symtomatic control of acute non serious diarrhoea, e.g.
 Relief of moderate to severe acute pain (or chronic pain                     travels’ diarrhoea (codeine)
     often in terminal illness)                                             Suppression of cough (codeine, dihydrocodeine,
 Brief relief of anxiety in serious and frightening diseases                  dextrometorphan)
     accompanied by pain (e.g. traumas but without                          Production of euphoria as well as pain relief in the
     commotio)                                                                 dying.
 Relief of dyspnoe in acute left ventricular failure, and in               NB: Opioid-induced nausea, vomiting and dysphoria
     terminal cases                                                            may interfere with any of the desired effects.
 Premedication for surgery
▼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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▼Papaveretum (Omnopon®) is a purified mixture of all opium alkaloids and it contains 50% morphine.
▼Diamprphine (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.

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-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.
▼ 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.

 CLASSIFICATION OF OPIOIDS BY ANALGESIC EFFICASY
Low efficacy for mild and moderate pain               High efficacy fore severe pain
codeine, dihydrocodeine, dextripropoxiphene,          alfentanil, buprenorphine, dextromoramide, diamorphine (heroin), fentanyl,
nalbuphine, oxycodone, pentazocine                    methadone, morphine, papaveretum (Omnopon®) pethidine (meperidine,
                                                      Lydol®), sufentanil, tramadol

 OPIOID ANTAGONISTS
▼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 t 1/2 (e.g. methadone). Naloxone is also used to counter
excess opioid effects after surgical analgesia or childbirth.
▼NALTREXONE (t1/2 4 h: active metabolite 13h) 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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