Analgetics
Physiology of pain
The word “pain” comes from the Latin: poena meaning punishment, a fine, a penalty. Pain is an unpleasant sensation; nociception[1] or nociperception[2] is a measurable physiological event of a type usually associated with pain and agony and suffering. A sensation of pain can exist in the absence of nociception: it can occur in response to both external perceived events (for example, seeing something) or internal cognitive events (for example, the phantom limb pain of an amputee). Pain is defined as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage” – International Association for the Study of Pain (IASP). Scientifically, pain (a subjective experience) is separate and distinct from nociception, the system which carries information, about inflammation, damage or near-damage in tissue, to the spinal cord and brain. Nociception frequently occurs without pain being felt and is below the level of consciousness. Despite it triggering pain and suffering, nociception is a critical component of the body‘s defense system. It is part of a rapid warning relay instructing the central nervous system to initiate motor neurons in order to minimize detected physical harm. Pain too is part of the body’s defense system; it triggers mental problem solving strategies that seek to end the painful experience, and it promotes learning, making repetition of the painful situation less likely.
Types of pain
Pain can be classified as acute or chronic. The distinction between acute and chronic pain is not based on its duration of sensation, but rather the nature of the pain itself. In general, physicians are more comfortable treating acute pain, which has as its source soft tissue damage, infection and/or inflammation.
Many physicians faced with patients who live with chronic pain have had no professional training in pain management. It is not regularly taught in medical school, and even recent legislation in some states to ensure that physicians receive continuing education in pain medicine and end-of-life care do not guarantee proper training in pain. In many states, there remains no legislation ensuring that licensed physicians, even those who work in hospital emergency rooms, have any pain management training whatsoever. Chronic pain has no time limit, often has no apparent cause and serves no apparent biological purpose. Chronic pain can trigger multiple psychological problems that confound both patient and health care provider, leading to feelings of helplessness and hopelessness. The most common causes of chronic pain include low-back pain, headache, recurrent facial pain, cancer pain, and arthritic pain. Published information on pain perpetuate myths that do a disservice to those who live with pain and many glossaries contradict one another.
- Chronic pain was originally defined as pain that has lasted 6 months or longer. It is now defined as “the disease of pain.” Its origin, duration, intensity, and specific symptoms vary. The one consistent fact of chronic pain is that, as a disease, it cannot be understood in the same terms as acute pain, and the failure to make this distinction (particularly in those who suffer chronic pain) has been and continues to be the cause of multi-dimensional suffering, depression, social isolation, and helplessness.
The experience of physiological pain can be grouped according to the source and related nociceptors (pain detecting neurons).
- Cutaneous pain is caused by injury to the skin or superficial tissues. Cutaneous nociceptors terminate just below the skin, and due to the high concentration of nerve endings, produce a well-defined, localized pain of short duration. Examples of injuries that produce cutaneous pain include paper cuts, minor cuts, minor (first degree) burns and lacerations.
- Somatic pain originates from ligaments, tendons, bones, blood vessels, and even nerves themselves. It is detected with somatic nociceptors. The scarcity of pain receptors in these areas produces a dull, poorly-localized pain of longer duration than cutaneous pain; examples include sprains and broken bones. Myofascial pain usually is caused by trigger points in muscles, tendons and fascia, and may be local or referred.
- Visceral pain originates from body’s viscera, or organs. Visceral nociceptors are located within body organs and internal cavities. The even greater scarcity of nociceptors in these areas produces pain that is usually more aching and of a longer duration than somatic pain. Visceral pain is extremely difficult to localize, and several injuries to visceral tissue exhibit “referred” pain, where the sensation is localized to an area completely unrelated to the site of injury. Myocardial ischaemia (the loss of blood flow to a part of the heart muscle tissue) is possibly the best known example of referred pain; the sensation can occur in the upper chest as a restricted feeling, or as an ache in the left shoulder, arm or even hand. “The brain freeze” is another example of referred pain, in which the vagus nerve is cooled by cold inside the throat. Referred pain can be explained by the findings that pain receptors in the viscera also excite spinal cord neurons that are excited by cutaneous tissue. Since the brain normally associates firing of these spinal cord neurons with stimulation of somatic tissues in skin or muscle, pain signals arising from the viscera are interpreted by the brain as originating from the skin. The theory that visceral and somatic pain receptors converge and form synapses on the same spinal cord pain-transmitting neurons is called “Ruch’s Hypothesis”.
- Phantom limb pain, a type of referred pain, is the sensation of pain from a limb that has been lost or from which a persoo longer receives physical signals. It is an experience almost universally reported by amputees and quadriplegics.
- Neuropathic pain, can occur as a result of injury or disease to the nerve tissue itself. This can disrupt the ability of the sensory nerves to transmit correct information to the thalamus, and hence the brain interprets painful stimuli even though there is no obvious or known physiologic cause for the pain. Neuropathic pain is, as stated above, the disease of pain. It is not the sole definition for chronic pain, but does meet its criteria.
Figure A:
Antinociceptive pathways are activated when pain signals in the spinothalamic tract reach the brain stem and thalamus. The periaqueductal gray matter and nucleus raphe magnus release endorphins and enkephalins. A series of physicochemical changes then produce inhibition of pain transmission in the spinal cord.
Figure B:
70% of endorphin and enkephalin receptors are in the presynaptic membrane of nociceptors. Thus, most of the pain signal is stopped before it reaches the dorsal horn. The signal is then further weakened by dynorphin activity in the spinal cord. The site of action of various analgesics is shown.
Figure C:
Dynorphin activation of alpha receptors on inhibitory interneurons causes the release of GABA. This causes hyperpolarisation of dorsal horn cells and inhibits further transmission of the pain signal.
Major Sources of Pain
|
Source |
Area Involved |
Characteristics |
Treatment |
|
Somatic |
body framework |
throbbing, stabbing |
narcotics, NSAIDS |
|
Visceral |
kidneys, intestines, liver |
aching, throbbing, sharp, crampy |
narcotics, NSAIDS |
|
Neuropathic |
Nerves |
burning, numbing, tingling |
antidepressants, anticonvulsants |
|
Sympathetically Mediated |
overactive sympathetic system |
no pain should be felt |
nerve blockers |
An analgesic (colloquially known as a painkiller) is any member of the diverse group of drugs used to relieve pain (achieve analgesia). This derives from Greek an-, “without”, and -algia, “pain”. Analgesic drugs act in various ways on the peripheral and central nervous system; they include paracetamol (acetaminophen), the nonsteroidal anti-inflammatory drugs (NSAIDs) such as the salicylates, narcotic drugs such as morphine, synthetic drugs with narcotic properties such as tramadol, and various others. Some other classes of drugs not normally considered analgesics are used to treat neuropathic pain syndromes; these include tricyclic antidepressants and anticonvulsants.
Opioid Analgesics—Morphine Type Source of opioids.
Papaver rhoeas L. Papaver somniferum L.
Morphine is an opium alkaloid. Besides morphine, opium contains alkaloids devoid of analgesic activity, e.g., the spasmolytic papaverine, that are also classified as opium alkaloids.
All semisynthetic derivatives (hydromorphone) and fully synthetic derivatives (pentazocine, pethidine = meperidine, l-methadone, and fentanyl) are collectively referred to as opioids. The high analgesic effectiveness of xenobiotic opioids derives from their affinity for receptors normally acted upon by endogenous opioids (enkephalins, в-endorphin, dynorphins; A).
Opioid receptors occur ierve cells. They are found in various brain regions and the spinal medulla, as well as in intramural nerve plexuses that regulate the motility of the alimentary and urogenital tracts. There are several types of opioid receptors, designated µ, д, к, that mediate the various opioid effects; all belong to the superfamily of G-proteincoupled receptors. Endogenous opioids are peptides that are cleaved from the precursors proenkephalin, pro-opiomelanocortin, and prodynorphin. All contain the amino acid sequence of the pentapeptides [Met]- or [Leu]-enkephalin (A). The effects of the opioids can be abolished by antagonists (e.g., naloxone; A), with the exception of buprenorphine.
Mode of action of opioids. Most neurons react to opioids with hyperpolarization, reflecting an increase in K+ conductance. Ca2+ influx into nerve terminals during excitation is decreased, leading to a decreased release of excitatory transmitters and decreased synaptic activity (A). Depending on the cell population affected, this synaptic inhibition translates into a depressant or excitant effect (B).
Effects of opioids (B). The analgesic effect results from actions at the level of the spinal cord (inhibition of nociceptive impulse transmission) and the brain (attenuation of impulse spread, inhibition of pain perception). Attention and ability to concentrate are impaired. There is a mood change, the direction of which depends on the initial condition. Aside from the relief associated with the abatement of strong pain, there is a feeling of detachment (floating sensation) and sense of well-being (euphoria), particularly after intravenous injection and, hence, rapid buildup of drug levels in the brain. The desire to re-experience this state by renewed administration of drug may become overpowering: development of psychological dependence. The atttempt to quit repeated use of the drug results in withdrawal signs of both a physical (cardiovascular disturbances) and psychological (restlessness, anxiety, depression)
nature. Opioids meet the criteria of “addictive” agents, namely, psychological and physiological dependence as well as a compulsion to increase the dose. For these reasons, prescription of opioids is subject to special rules (Controlled Substances
tramadol, may be prescribed in the usual manner, because of their lesser potential for abuse and development of dependence.
Differences between opioids regarding efficacy and potential for dependence probably reflect differing affinity and intrinsic activity profiles for the individual receptor subtypes. A given sustance does not necessarily behave as an agonist or antagonist at all receptor subtypes, but may act as an agonist at one subtype and as a partial agonist/ antagonist or as a pure antagonist at another. The abuse potential is also determined by kinetic properties, because development of dependence is favored by rapid build-up of brain concentrations. With any of the high-efficacy opioid analgesics, overdosage is likely to result in respiratory paralysis (impaired sensitivity of medullary chemoreceptors to CO2). The maximally possible extent of respiratory depression is thought to be less in partial agonist/ antagonists at opioid receptors (pentazocine, nalbuphine). The cough-suppressant (antitussive) effect produced by inhibition of the cough reflex is independent of the effects on nociception or respiration (antitussives: codeine. noscapine). Stimulation of chemoreceptors in the area postrema results in vomiting, particularly after first-time administration or in the ambulant patient. The emetic effect disappears with repeated use because a direct inhibition of the emetic center then predominates, which overrides the stimulation of area postrema chemoreceptors. Opioids elicit pupillary narrowing (miosis) by stimulating the parasympathetic portion (Edinger-Westphal nucleus) of the oculomotor nucleus. Peripheral effects concern the motility and tonus of gastrointestinal smooth muscle; segmentation is enhanced, but propulsive peristalsis is inhibited. The tonus of sphincter muscles is raised markedly. In this fashion, morphine elicits the picture of spastic constipation. The antidiarrheic effect is used therapeutically (loperamide). Gastric emptying is delayed (pyloric spasm) and drainage of bile and pancreatic juice is impeded, because the sphincter of Oddi contracts. Likewise, bladder function is affected; specifically bladder emptying is impaired due to increased tone of the vesicular sphincter. Uses: The endogenous opioids (metenkephalin, leuenkephalin, в-endorphin) cannot be used therapeutically
because, due to their peptide nature, they are either rapidly degraded or excluded from passage through the bloodbrain barrier, thus preventing access to their sites of action even after parenteral administration (A).
Morphine can be given orally or parenterally, as well as epidurally or intrathecally in the spinal cord. The opioids heroin and fentanyl are highly lipophilic, allowing rapid entry into the CNS. Because of its high potency, fentanyl is suitable for transdermal delivery (A). In opiate abuse, “smack” (“junk,” “jazz,” “stuff,” “China white;” mostly heroin) is self administered by injection (“mainlining”) so as to avoid first-pass metabolism and to achieve a faster rise in brain concentration. Evidently, psychic effects (“kick,” “buzz,” “rush”) are especially intense with this route of administration. The user may also resort to other more unusual routes: opium can be smoked, and heroin can be taken as snuff (B).
Metabolism (C). Like other opioids bearing a hydroxyl group, morphine is conjugated to glucuronic acid and eliminated renally. Glucuronidation of the OH-group at position 6, unlike that at position 3, does not affect affinity. The extent to which the 6-glucuronide contributes to the analgesic action remains uncertain at present. At any rate, the activity of this polar metabolite needs to be taken into account in renal insufficiency (lower dosage or longer dosing interval).
Tolerance. With repeated administration of opioids, their CNS effects can lose intensity (increased tolerance). In the course of therapy, progressively larger doses are needed to achieve the same degree of pain relief. Development of tolerance does not involve the peripheral effects, so that persistent constipation during prolonged use may force a discontinuation of analgesic therapy however urgently needed. Therefore, dietetic and pharmacological measures should be taken prophylactically to prevent constipation, whenever prolonged administration of opioid drugs is indicated. Morphine antagonists and partial agonists. The effects of opioids can be
abolished by the antagonists naloxone or naltrexone (A), irrespective of the receptor type involved. Given by itself, neither has any effect iormal subjects; however, in opioid-dependent subjects, both precipitate acute withdrawal signs.
Because of its rapid presystemic elimination, naloxone is only suitable for parenteral use. Naltrexone is metabolically more stable and is given orally. Naloxone is effective as antidote in the treatment of opioid-induced respiratory paralysis. Since it is more rapidly eliminated than most opioids, repeated doses may be needed. Naltrexone may be used as an adjunct in withdrawal therapy. Buprenorphine behaves like a partial agonist/antagonist at µ-receptors. Pentazocine is an antagonist at µ-receptors and an agonist at к-receptors (A). Both are classified as “low-ceiling” opioids (B), because neither is capable of eliciting the maximal analgesic effect obtained with morphine or meperidine. The antagonist action of partial agonists may result in an initial decrease in effect of a full agonist during changeover to the latter. Intoxication with buprenorphine cannot be reversed with antagonists, because the drug dissociates only very slowly from the opioid receptors and competitive occupancy of the receptors cannot be achieved as fast as the clinical situation demands. Opioids in chronic pain: In the management of chronic pain, opioid plasma concentration must be kept continuously in the effective range, because a fall below the critical level would cause the patient to experience pain. Fear of this situation would prompt intake of higher doses thaecessary. Strictly speaking, the aim is a prophylactic analgesia.
Like other opioids (hydromorphone, meperidine, pentazocine, codeine), morphine is rapidly eliminated, limiting its duration of action to approx. 4 h. To maintain a steady analgesic effect, these drugs need to be given every 4 h. Frequent dosing, including at nighttime, is a major inconvenience for chronic pain patients. Raising the individual
dose would permit the dosing interval to be lengthened; however, it would also lead to transient peaks above the therapeutically required plasma level with the attending risk of unwanted toxic effects and tolerance development. Preferred alternatives include the use of controlled-release preparations of morphine, a fentanyl adhesive patch, or a longer-acting opioid such as l-methadone. The kinetic properties of the latter, however, necessitate adjustment of dosage in the course of treatment, because low dosage during the first days of treatment fails to provide pain relief, whereas high dosage of the drug, if continued, will lead to accumulation into a toxic concentration range (C). When the oral route is unavailable opioids may be administered by continuous infusion (pump) and when appropriate under control by the patient – advantage: constant therapeutic plasma level; disadvantage: indwelling catheter. When constipation becomes intolerable morphin can be applied near the
spinal cord permitting strong analgesic effect at much lower total dosage.
Non-narcotic Analgetics
Paracetamol and NSAIDs
The exact mechanism of action of paracetamol is uncertain, but it appears to be acting centrally. Aspirin and the NSAIDs inhibit cyclooxygenase, leading to a decrease in prostaglandin production; this reduces pain and also inflammation (in contrast to paracetamol and the opioids). Paracetamol has few side effects, but dosing is limited by possible hepatotoxicity (potential for liver damage). NSAIDs may predispose to peptic ulcers, renal failure, allergic reactions, and hearing loss. They may also increase the risk of hemorrhage by affecting platelet function. The use of certain NSAIDs in children under 16 suffering from viral illness may contribute to Reye’s syndrome.
Paracetamol or acetaminophen, is a common analgesic and antipyretic drug that is used for the relief of fever, headaches, and other minor aches and pains. Paracetamol is also useful in managing more severe pain, allowing lower dosages of additional non-steroidal anti-inflammatory drugs (NSAIDs) or opioid analgesics to be used, thereby minimizing overall side-effects. It is a major ingredient iumerous cold and flu medications, as well as many prescription analgesics. It is considered safe for human use in recommended doses, but because of its wide availability, deliberate or accidental overdoses are fairly common.
In ancient and medieval times, known antipyretic agents were compounds contained in white willow bark (a family of chemicals known as salicins, which led to the development of aspirin), and compounds contained in cinchona bark. Cinchona bark was also used to create the anti-malaria drug quinine. Quinine itself also has antipyretic effects. Efforts to refine and isolate salicin and salicylic acid took place throughout the middle- and late-19th century, and was accomplished by Bayer chemist Felix Hoffmann (this was also done by French chemist Charles Frédéric Gerhardt 40 years earlier, but he abandoned the work after deciding it was too impractical).When the cinchona tree became scarce in the 1880s, people began to look for alternatives. Two alternative antipyretic agents were developed in the 1880s: acetanilide in 1886 and phenacetin in 1887. Harmon Northrop Morse first synthesized paracetamol via the reduction of p-nitrophenol with tin in glacial acetic acid in 1878, however, paracetamol was not used medically for another 15 years. In 1893, paracetamol was discovered in the urine of individuals who had taken phenacetin, and was concentrated into a white, crystalline compound with a bitter taste. In 1899, paracetamol was found to be a metabolite of acetanilide. This discovery was largely ignored at the time. Paracetamol has long been suspected of having a similar mechanism of action to aspirin because of the similarity in structure. That is, it has been assumed that paracetamol acts by reducing production of prostaglandins, which are involved in the pain and fever processes, by inhibiting the cyclooxygenase (COX) enzyme as aspirin does. However, there are important differences between the effects of aspirin and those of paracetamol. Prostaglandins participate in the inflammatory response which is why aspirin has been known to trigger symptoms in asthmatics, but paracetamol has no appreciable anti-inflammatory action and hence does not have this side-effect. Furthermore, the COX enzyme also produces thromboxanes, which aid in blood clotting — aspirin reduces blood clotting, but paracetamol does not. Finally, aspirin and the other NSAIDs commonly have detrimental effects on the stomach lining, where prostaglandins serve a protective role, but, in recommended doses, paracetamol does not. Indeed, while aspirin acts as an irreversible inhibitor of COX and directly blocks the enzyme’s active site, paracetamol indirectly blocks COX, and this blockade is ineffective in the presence of peroxides. This might explain why paracetamol is effective in the central nervous system and in endothelial cells but not in platelets and immune cells which have high levels of peroxides.
In 2002 it was reported that paracetamol selectively blocks a variant of the COX enzyme that was different from the then known variants COX-1 and COX-2. This isoenzyme, which is only expressed in the brain and the spinal cord, is now referred to as COX-3. Its exact mechanism of action is still poorly understood, but future research may provide further insight into how it works. A single study has shown that administration of paracetamol increases the bioavailability of serotonin (5-HT) in rats, but the mechanism is unknown and untested in humans. In 2006, it was shown that paracetamol is converted to N-arachidonoylphenolamine, a compound already known (AM404) as an endogenous cannabinoid. As such, it activates the CB1 cannabinoid receptor; a CB(1) receptor antagonist completely blocks the analgesic action of paracetamol. Paracetamol is metabolized primarily in the liver, where most of it (60–90% of a therapeutic dose) is converted to inactive compounds by conjugation with sulfate and glucuronide, and then excreted by the kidneys. Only a small portion (5–10% of a therapeutic dose) is metabolized via the hepatic cytochrome P450 enzyme system (specifically CYP2E1); the toxic effects of paracetamol are due to a minor alkylating metabolite (N-acetyl-p-benzo-quinone imine, abbreviated as NAPQI) that is produced through this enzyme, not paracetamol itself or any of the major metabolites. The metabolism of paracetamol is an excellent example of toxication, because the metabolite NAPQI is primarily responsible for toxicity rather than paracetamol itself. At usual doses, the toxic metabolite NAPQI is quickly detoxified by combining irreversibly with the sulfhydryl groups of glutathione to produce a non-toxic conjugate that is eventually excreted by the kidneys.
Paracetamol is contained in many preparations (both over-the-counter and prescription-only medications). In some animals, for example cats, small doses are toxic. Because of the wide availability of paracetamol there is a large potential for overdose and toxicity.[9] Without timely treatment, paracetamol overdose can lead to liver failure and death within days. It is sometimes used in suicide attempts by those unaware of the prolonged timecourse and high morbidity (likelihood of significant illness) associated with paracetamol-induced toxicity in survivors. The toxic dose of paracetamol is highly variable. In adults, single doses above
Aspirin, or acetylsalicylic acid is a drug in the family of salicylates, often used as an analgesic (to relieve minor aches and pains), antipyretic (to reduce fever), and as an anti-inflammatory. It also has an antiplatelet (“blood-thinning”) effect and is used in long-term, low doses to prevent heart attacks and cancer.
Low-dose, long-term aspirin use irreversibly blocks the formation of thromboxane A2 in platelets, producing an inhibitory effect on platelet aggregation. This anticoagulant property makes it useful for reducing the incidence of heart attacks. Aspirin produced for this purpose often comes in 75 or 81 mg, dispersible tablets and is sometimes called “junior aspirin” or “baby aspirin.” New evidence suggests that baby aspirin may not be as effective in preventing heart attacks and cerebrovascular accidents as previously thought. High doses of aspirin are also given immediately after an acute heart attack. These doses may also inhibit the synthesis of prothrombin and may, therefore, produce a second and different anticoagulant effect, but this is not well understood.
Its primary, undesirable side-effects, especially in higher doses, are gastrointestinal distress (including ulcers and stomach bleeding) and tinnitus. Another side-effect, due to its anticoagulant properties, is increased bleeding in menstruating women. Because there appears to be a connection between aspirin and Reye’s syndrome, aspirin is no longer used to control flu-like symptoms or the symptoms of chickenpox in minors. Aspirin was the first-discovered member of the class of drugs known as non-steroidal, anti-inflammatory drugs (NSAIDs), not all of which are salicylates, though they all have similar effects and a similar action mechanism.
Aspirin, as with many older drugs, has proven to be useful in many conditions. Despite its well-known toxicity it is widely used, since physicians are familiar with its properties. Indications for its use include:
· Fever
· Pain (especially useful for some forms of arthritis, osteoid osteoma, and chronic pain)
· Migraine
· Rheumatic fever (drug of choice)
· Kawasaki disease (along with IVIG)
· Acute myocardial infarction
In addition, aspirin is recommended (low dose, 75-81 mg daily) for the prevention of:
· Myocardial infarction — in patients with either documented coronary artery disease or at elevated risk of cardiovascular disease
· Stroke — as secondary prevention (i.e. to prevent recurrence)
For adults doses of 300 to 1000 mg are generally taken four times a day for fever or arthritis, with a maximum dose of 8000 mg a day. The correct dose of aspirin depends on the disease process that is being treated. For instance, for the treatment of rheumatic fever, doses near the maximal daily dose have been used historically. For the prevention of myocardial infarction in someone with documented or suspected coronary artery disease, doses as low as 75 mg daily (or possibly even lower) are sufficient. For those under 12 years of age, the dose previously varied with the age, but aspirin is no longer routinely used in children due to the association with Reye’s syndrome; paracetamol or other NSAIDs, such as Ibuprofen, are now being used instead. Kawasaki disease remains one of the few indications for aspirin use in children with aspirin initially started at 7.5-12.5 mg/kg body weight taken four times a day for up to two weeks and then continued at 5 mg/kg once daily for a further six to eight weeks.
· Aspirin should be avoided by those known to be allergic to ibuprofen or naproxen.
· Caution should be exercised in those with asthma or NSAID-precipitated bronchospasm.
· It is generally recommended that one seek medical help if symptoms do not improve after a few days of therapy.
· Caution should be taken in patients with kidney disease, peptic ulcers, mild diabetes, gout or gastritis; manufacturers recommend talking to one’s doctor before using this medicine.
· Taking aspirin with alcohol increases the chance of gastrointestinal hemorrhage (stomach bleeding).
· Children, including teenagers, are discouraged from using aspirin in cold or flu symptoms as this has been linked with Reye’s syndrome.
· Patients with hemophilia or other bleeding tendencies should not take salicylates.
· Some sources recommend that patients with hyperthyroidism avoid aspirin because it elevates T4 levels.
Common side-effects
· Gastrointestinal complaints (stomach upset, dyspepsia, heartburn, small blood loss). To help avoid these problems, it is recommended that aspirin be taken at or after meals. Undetected blood loss may lead to hypochromic anemia.
· Severe gastrointestinal complaints (gross bleeding and/or ulceration), requiring discontinuation and immediate treatment. Patients receiving high doses and/or long-term treatment should receive gastric protection with high-dosed antacids, ranitidine or omeprazole.
· Frequently, central effects (dizziness, tinnitus, hearing loss, vertigo, centrally mediated vision disturbances, and headaches). The higher the daily dose is, the more likely it is that central nervous system side-effects will occur.
· Sweating, seen with high doses, independent from antipyretic action
· Long-term treatment with high doses (arthritis and rheumatic fever): often increased liver enzymes without symptoms, rarely reversible liver damage. The potentially fatal Reye’s syndrome may occur, if given to pediatric patients with fever and other signs of infections. The syndrome is due to fatty degeneration of liver cells. Up to 30 percent of those afflicted will eventually die. Prompt hospital treatment may be life-saving.
· Chronic nephritis with long-term use, usually if used in combination with certain other painkillers. This condition may lead to chronic renal failure.
· Prolonged and more severe bleeding after operations and post-traumatic for up to 10 days after the last aspirin dose. If one wishes to counteract the bleeding tendency, fresh thrombocyte concentrate will usually work.
· Skin reactions, angioedema, and bronchospasm have all been seen infrequently.
· Patients that have the genetic disease known as Glucose-6-Phosphate Dehydrogenase deficiency (G6PD) should avoid this drug as it is known to cause hemolytic anemia in large doses depending on the severity of the disease.
The toxic dose of aspirin is generally considered greater than 150 mg per kg of body mass. Moderate toxicity occurs at doses up to 300 mg/kg, severe toxicity occurs between 300 to 500 mg/kg, and a potentially lethal dose is greater than 500 mg/kg.[13] This is the equivalent of many dozens of the common 325 mg tablets, depending on body weight. Note that children cannot tolerate as much aspirin per unit body weight as adults can, even when aspirin is indicated. Label-directions should be followed carefully. COX-2 selective inhibitor is a form of Non-steroidal anti-inflammatory drug (NSAID) that directly targets COX-2, an enzyme responsible for inflammation and pain.
Selectivity for COX-2 reduces the risk of peptic ulceration, and is the main feature of celecoxib, rofecoxib and other members of this drug class. Cox-2-selectivity does not seem to affect other adverse-effects of NSAIDs (most notably an increased risk of renal failure), and some results have aroused the suspicion that there might be an increase in the risk for heart attack, thrombosis and stroke by a relative increase in thromboxane. Rofecoxib was taken off the market in 2004 because of these concerns. In the course of the search for a specific inhibitor of the negative effects of prostaglandins which spared the positive effects, it was discovered that prostaglandins could indeed be separated into two general classes which could loosely be regarded as “good prostaglandins” and “bad prostaglandins”, according to the structure of a particular enzyme involved in their synthesis, cyclooxygenase. Prostaglandins whose synthesis involves the cyclooxygenase-I enzyme, or COX-1, are responsible for maintenance and protection of the gastrointestinal tract, while prostaglandins whose synthesis involves the cyclooxygenase-II enzyme, or COX-2, are responsible for inflammation and pain. The existing nonsteroidal antiinflammatory drugs (NSAIDs) differ in their relative specificities for COX-2 and COX-1; while aspirin is equipotent at inhibiting COX-2 and COX-1 enzymes in vitro and ibuprofen demonstrates a sevenfold greater inhibition of COX-1, other NSAIDs appear to have partial COX-2 specificity, particularly meloxicam (Mobic). Studies of meloxicam 7.5 mg per day for 23 days find a level of gastric injury similar to that of a placebo, and for meloxicam 15 mg per day a level of injury lower than that of other NSAIDs; however, in clinical practice meloxicam can still cause some ulcer complications. A search for COX-2-specific inhibitors resulted in promising candidates such as valdecoxib, celecoxib, and rofecoxib, marketed under the brand names Bextra, Celebrex, and Vioxx respectively.
Combinations
Analgesics are frequently used in combination, such as the paracetamol and codeine preparations found in many non-prescription pain relievers. They can also be found in combination with vasoconstrictor drugs such as pseudoephedrine for sinus-related preparations, or with antihistamine drugs for allergy sufferers. The use of paracetamol, as well as aspirin, ibuprofen, naproxen, and other NSAIDS concurrently with weak to mid-range opiates (up to about the hydrocodone level) has been shown to have beneficial synergistic effects by combating pain at multiple sites of action–NSAIDs reduce inflammation which, in some cases, is the cause of the pain itself while opiates dull the perception of pain–thus, in cases of mild to moderate pain caused in part by inflammation, it is generally recommended that the two are prescribed together.
Topical or systemic
Topical analgesia is generally recommended to avoid systemic side-effects. Painful joints, for example, may be treated with an ibuprofen– or diclofenac-containing gel; capsaicin also is used topically. Lidocaine and steroids may be injected into painful joints for longer-term pain relief. Lidocaine is also used for painful mouth sores and to numb areas for dental work and minor medical procedures.
Local Anesthetics
Local anesthetics reversibly inhibit impulse generation and propagation ierves. In sensory nerves, such an effect is desired when painful procedures must be performed, e.g., surgical or dental operations.
Mechanism of action. Nerve impulse conduction occurs in the form of an action potential, a sudden reversal in resting transmembrane potential lasting less than 1 ms. The change in potential is triggered by an appropriate stimulus and involves a rapid influx of Na+ into the interior of the nerve axon (A).
This inward flow proceeds through a channel, a membrane pore protein, that, upon being opened (activated), permits rapid movement of Na+ down a chemical gradient ([Na+]ext ~
Mechanism-specific adverse effects.
Since local anesthetics block Na+ influx not only in sensory nerves but also in other excitable tissues, they are applied locally and measures are taken to impede their distribution into the body. Too rapid entry into the circulation would lead to unwanted systemic reactions such as:
_ blockade of inhibitory CNS neurons,
manifested by restlessness and seizures ; general paralysis with respiratory arrest after
higher concentrations.
_ blockade of cardiac impulse conduction, as evidenced by impaired AV conduction or cardiac arrest (countermeasure: injection of epinephrine).
Depression of excitatory processes in the heart, while undesired during local anesthesia, can be put to therapeutic use in cardiac arrhythmias.
Forms of local anesthesia. Local anesthetics are applied via different routes, including infiltration of the tissue (infiltration anesthesia) or injectioext to the nerve branch carrying fibers from the region to be anesthetized (conduction anesthesia of the nerve, spinal anesthesia of segmental dorsal roots), or by application to the surface of the skin or mucosa (surface anesthesia). In each case, the local anesthetic drug is required to diffuse to the nerves concerned from a depot
placed in the tissue or on the skin. High sensitivity of sensory nerves, low sensitivity of motor nerves. Impulse conduction in sensory nerves is inhibited at a concentration lower than that needed for motor fibers. This difference may be due to the higher impulse frequency and longer action potential duration iociceptive, as opposed to motor, fibers. Alternatively, it may be related to the thickness of sensory and motor nerves, as well as to the distance betweeodes of Ranvier. In saltatory
impulse conduction, only the nodal membrane is depolarized. Because depolarization can still occur after blockade of three or four nodal rings, the area exposed to a drug concentration sufficient to cause blockade must be larger for motor fiber. This relationship explains why sensory stimuli that are conducted via myelinated Aд-fibers are affected later and to a lesser degree than are stimuli conducted via unmyelinated C-fibers. Since autonomic postganglionic fibers lack a myelin sheath, they are particularly susceptible to blockade by local anesthetics. As a result, vasodilation ensues in the anesthetized region, because sympathetically driven vasomotor tone decreases. This local vasodilation is undesirable .
Diffusion and Effect
During diffusion from the injection site (i.e., the interstitial space of connective tissue) to the axon of a sensory nerve, the local anesthetic must traverse the perineurium. The multilayered perineurium is formed by connective tissue cells linked by zonulae occludentes and therefore constitutes a closed lipophilic barrier. Local anesthetics in clinical use are usually tertiary amines; at the pH of interstitial fluid, these exist partly as the neutral lipophilic base (symbolized by particles marked with two red dots) and partly as the protonated form, i.e., amphiphilic cation (symbolized by particles marked with one blue and one red dot). The uncharged form can penetrate the perineurium and enters the endoneural space, where a fraction of the drug molecules regains a positive charge in keeping with the local pH. The same process is repeated when the drug penetrates the axonal membrane (axolemma) into the axoplasm, from which it exerts its action on the sodium channel, and again when it diffuses out of the endoneural space through the unfenestrated endothelium of capillaries into the blood. The concentration of local anesthetic at the site of action is, therefore, determined by the speed of penetration into the endoneurium and the speed of diffusion into the capillary blood. In order to ensure a sufficiently fast build-up of drug concentration at the site of action, there must be a correspondingly large concentration gradient between drug depot in the connective tissue and the endoneural space. Injection of solutions of low concentration will fail to produce an effect; however, too high concentrations must also be avoided because of the danger of intoxication resulting from too rapid systemic absorption into the blood.To ensure a reasonably long-lasting local effect with minimal systemic action, a vasoconstrictor (epinephrine, less frequently norepinephrine or a vasopressin derivative; is often co-administered in an attempt to confine the drug to its site of action. As blood flow is diminished, diffusion from the endoneural space into the capillary blood decreases because the critical concentration gradient between endoneural space and blood quickly becomes small when inflow of drug-free blood is
reduced. Addition of a vasoconstrictor, moreover, helps to create a relative ischemia in the surgical field. Potential disadvantages of catecholamine-type vasoconstrictors include reactive hyperemia following washout of the constrictor agent and cardiostimulation when epinephrine enters the systemic circulation. In lieu of epinephrine, the vasopressin analogue felypressin can be used as an adjunctive vasoconstrictor (less pronounced reactive hyperemia, no arrhythmogenic action, but danger of coronary constriction). Vasoconstrictors must not be applied in local anesthesia involving the appendages (e.g., fingers, toes).
Characteristics of chemical structure.
Local anesthetics possess a uniform structure. Generally they are secondary or tertiary amines. The nitrogen is linked through an intermediary chain to a lipophilic moiety — most often an aromatic ring system. The amine function means that local anesthetics exist either as the neutral amine or positively charged ammonium cation, depending upon their dissociation constant (pKa value) and the actual pH value. The pKa of typical local anesthetics lies between 7.5 and 9.0. The pka indicates the pH value at which 50% of molecules carry a proton. In its protonated form, the molecule possesses both a polar hydrophilic moiety (protonated nitrogen) and an apolar lipophilic moiety (ring system)—it is amphiphilic. Graphic images of the procaine molecule reveal that the positive charge does not have a punctate localization at the N atom; rather it is distributed, as shown by the potential on the van der Waals’ surface. The non-protonated form (right) possesses a negative partial charge in the region of the ester bond and at the amino group at the aromatic ring and is neutral to slightly positively charged (blue) elsewhere. In the protonated form (left), the positive charge is prominent and concentrated at the amino group of the side chain (dark blue). Depending on the pKa, 50 to 5% of the drug may be present at physiological pH in the uncharged lipophilic form. This fraction is important because it represents the lipid membrane-permeable form of the local anesthetic, which must take on its cationic amphiphilic form in order to exert its action. Clinically used local anesthetics are either esters or amides.
This structural element is unimportant for efficacy; even drugs containing a methylene bridge, such as chlorpromazine or imipramine, would exert a local anesthetic effect with appropriate application. Ester-type local anesthetics are subject to inactivation by tissue esterases. This is advantageous because of the diminished danger of systemic intoxication. On the other hand, the high rate of bioinactivation and, therefore, shortened duration of action is a disadvantage. Procaine cannot be used as a surface anesthetic because it is inactivated faster than it can penetrate the dermis or mucosa.
The amide type local anesthetic lidocaine is broken down primarily in the liver by oxidative N-dealkylation. This step can occur only to a restricted extent in prilocaine and articaine because both carry a substituent on the Catom adjacent to the nitrogen group. Articaine possesses a carboxymethyl group on its thiophen ring. At this position, ester cleavage can occur, resulting in the formation of a polar -COO– group,
loss of the amphiphilic character, and conversion to an inactive metabolite. Benzocaine (ethoform) is a member of the group of local anesthetics lacking a nitrogen that can be protonated at physiological pH. It is used exclusively as a surface anesthetic. Other agents employed for surface anesthesia include the uncharged polidocanol and the catamphiphilic cocaine, tetracaine, and lidocaine.
Pharmacology and Toxicology of Cocaine
Cocaine (benzoylmethylecgonine, C17H21NO4) is an alkaloid prepared from the leaves of the Erythroxylon coca plant, which grows mainly in
Coca leaves were first used in medicine in 1596, but it was not until the mid 1800’s that cocaine was extracted. Freud reported the effects of cocaine in 1884, and it was subsequently utilised in ophthalmology and dentistry as a local anaesthetic.
Cocaine hydrochloride is prepared by dissolving the alkaloid in hydrochloric acid, forming a water soluble salt. It is sold illicitly as a white powder, or as crystals or granules.
Street names include ‘coke’, ‘charlie’, ‘nose-candy’, ‘snow’ and ‘wash’. This form of cocaine can be ‘freebased’, prior to smoking, in which it is dissolved in ether or ammonia. The ‘freebase’ remains after the volatile substance has evaporated. Although this form of cocaine was popular in the late 1970s, a further refinement of this process became more prominent in the
Crack cocaine is produced when cocaine hydrochloride is mixed with sodium bicarbonate (baking soda) and water, and then heated. On cooling, ‘rocks’ are precipitated, and these are smoked in crack pipes, or are heated on foil with the vapour inhaled. Crack is an extremely ‘pure’ form of an already ‘pure’ substance (in comparison with other drugs of abuse such as amphetamines).
Cocaine can be administered as a drug of abuse in the following ways,
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Cocaine hydrochloride – snorting (intranasal), smoking, intravenous (including being mixed with heroin (‘speedball’ or ‘snowball’)), ingestion, application to genitalia |
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Crack cocaine – inhalation of vapour from heated foil or pipe |
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Coca leaves – chewed/ ingested |
In the
Cocaine addicts are required to be notified by doctors to the Chief Medical Officer under Regulation 3 of the Misuse of Drugs (Notification of and supply to Addicts) Regulations 1973, and Regulation 4 prevents doctors from prescribing cocaine unless they are licensed to do so by the Home Secretary. However, this does not apply to those treating organic disease or injury.
Epidemiology
Epidemiological data of drug misuse is not freely available in the same way that it is in the
The following points of note can be extracted from the data,
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32% of the adult population is thought to have used a drug at some point in their life (11% in the last year, 6% in the last month) |
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49% of under 30s report having used a drug (16% within the last month) |
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the highest adult prevalence is in the 16-19 year age group – 31% using drugs on a regular basis |
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drug use peaks at the end of the teens |
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male users outstrip female users by 2:1 |
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unskilled workers abuse drugs more than other social classes, and chose more dangerous routes of administration |
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the highest prevalence is found among the unemployed – 40% report drug use within the last year |
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ethnic differences in drug abuse were negligible overall, but the type of drug abused varied (e.g. whites were found to abuse amphetamines and LSD more than Afro-Caribbeans). |
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Drug use amongst Indians, Pakistanis and Bangladeshis was appreciably lower |
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48% of male prisoners use drugs whilst in prison |
In terms of cocaine and crack use, the data is often grouped with heroin use, and is not always easy to separate out,
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1% of 20-50 year olds had used these drugs |
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9% of 16-29 year olds had taken these drugs, with cocaine representing a large proportion of this |
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cocaine use is on the increase among young people, particularly in the |
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cocaine use has increased to 3% of 16-44 year olds – |
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a recent ‘Time Out’ readers poll found that 3% used cocaine regularly, with 45% having taken it at least once (compared to 2% and 6% respectively for crack) |
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heavy cocaine users spent £100 per day to support their habit |
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regular crack cocaine users could spend over £1000 over a weekend on 10g of the drug |
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cocaine related deaths are increasing – |
American data indicate that 23.7 million people used cocaine between 1990-1, nearly 4 million of which were using crack. (Cone 1993). Mortality from cocaine abuse has also risen, and cocaine accounts for the most frequent substance related deaths.
Pharmacokinetics
Cocaine has a half life of 40-50 minutes, and it’s effects on the body are felt rapidly, peaking after 15-20 minutes when ‘snorted’, and wearing off by 1.5 hours. When injected or ‘freebased’, or when crack is smoked, the effects are almost instantaneous, and last for only 15 minutes or so.Cocaine is metabolised to nearly a dozen pharmacologically inactive metabolites, the most important being benzoylecgonine and ecgonine methyl ester, primarily in the liver by spontaneous hydrolysis. (Casale et al 1994). Plasma cholinesterase also hydrolyses cocaine to ecgonine, and approximately 20% of the drug is excreted untouched into the urine. Both cocaine and its metabolites may be detected in urine up to 15 days after last administration by a chronic user. Cocaethylene is the ethylbenzoylecgonine form of cocaine produced in the presence of ethanol, resulting from transesterification by hepatic enzymes. (da Matta Chasin et al 2000 p.2). It is pharmacologically active, and it is formed at significantly lower concentrations than either of its parent substances.
Mechanisms of Action
Cocaine is a central nervous system stimulant, which gives rise to feelings of euphoria, excitement, increased motor activity and a feeling of being energised. Its principal mode of action is the blockade of the transporter protein that is responsible for the reuptake of monoamines (i.e. noradrenaline, serotonin and most importantly dopamine) into presynaptic terminals of neurons releasing these neurotransmitters. The result is that increased concentrations of these monoamines are found in the synaptic space, and their effects are potentiated. Blockage of the dopamine-reuptake transporter protein gives rise to the characteristic ‘high’ of cocaine. Knockout mice that do not have the gene encoding for this transporter protein are immune to the effects of cocaine, and studies have attempted to identify the exact dopamine receptor subtype on the post-synaptic neuron that is responsible for modulating the effects of cocaine. It appears that the D2 subtype modulates cravings associated with cocaine dependence and drug seeking behaviour, whilst the D1 subtype may modulate feelings of satiety, opening up possibilities for therapeutic targeting of these receptors to treat cocaine dependence and abuse. (Leshner 1996 pp.128-9). Dopamine hyperactivity as a result of cocaine administration is particularly important in the nigrostriatal dopaminergic system, which incorporates the limbic system of the brain – the ‘pleasure centre’. The activation of the limbic system by the drug gives rise to the intense euphoria, but in the chronic user, monoamine neurotransmitters are depleted, triggering a reactive lowering of mood or depression (serotonin depletion?), as well as disturbed sleep and eating cycles. Body temperature control is adversely affected, and depletion of dopamine has been linked to the onset of schizophrenia in susceptible individuals. In high doses, cocaine can cause tremors and convulsions via its effects on the cortex and brainstem, and can lead to respiratory and vasomotor depression. O’Dell et al (2000 p.677) speculate that cocaine activation of serotonin (2) receptors may be responsible for mediating convulsions. Chronic users can experience hallucinations, delusions and paranoia. Peripherally, cocaine potentiates noradrenaline action, and produces the typical ‘fight or flight’ sympathetic response of tachycardia, hypertension, pupillary dilatation and peripheral vasoconstriction. Table 1 below lists the effects of cocaine.
Physical and Psychological Effects of Cocaine (Sources: Stark et al 1996, Stark 1999, Wetli (1985))
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Dose |
Physical Effects |
Psychological Effects |
Initial Low Doses |
Tachycardia, tachypnoea, hypertension, Dilated pupils (& flattened lenses), sweating, reduced appetite, reduced need for sleep, reduced lung function, dry mouth, impaired motor control & performance of delicate skills and driving |
Euphoria, sense of well being, impaired reaction time and attention span, impaired learning of new skills |
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Increased doses |
Seizures, cardiac arrhythmias, myocardial infarction, stroke, respiratory arrest |
Anxiety, irritability, insomnia, depression, paranoia, aggressiveness, impulsivity, delusions, agitated/ excited delirium, reduced psychomotor function |
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Chronic Use |
Erosions, necrosis and perforation of nasal septum, anosmia, rhinorrhoea and nasal eczema (snorting), chest pains, muscle spasms, sexual impotence, weight loss, malnutrition, vascular disease |
Dependence, disturbed eating and sleeping patterns |
Therapeutic Uses of Cocaine
Cocaine is used as a surface local anaesthetic (it blocks Na+-K+ activated ATPase across adrenergic neuron cell membranes), particularly in Ear, Nose and Throat (ENT) surgery. It is also sometimes used in palliative care of terminally ill patients.
