Analgesics

What Are Analgesics? Simply put, analgesics are a class of drugs used to relieve pain. The pain relief induced by analgesics occurs either by blocking pain signals going to the brain or by interfering with the brain's interpretation of the signals, without producing anesthesia or loss of consciousness. There are basically two kinds of analgesics: non-narcotics and narcotics. It should be noted that some references include aspirin and other non-steroidal anti-inflammatory drugs (NSAIDS) in the class of analgesics, because they have some analgesic properties. Aspirin and NSAIDS primarily have an anti-inflammatory effect, as opposed to being solely analgesic. Non-Narcotic Analgesics Acetaminophen is the most commonly used over-the-counter, non-narcotic analgesic. Acetaminophen is a popular pain-reliever because it is both effective for mild to moderate pain relief and relatively inexpensive. It must be emphasized though that the safety of acetaminophen is tied to proper use of the drug (use according to specific prescribing instructions). If acetaminophen is not used according to the directions on the label, serious side effects and possible fatal consequences can occur. For example, taking more than 4000 mg/day or using it longterm can increase the risk of liver damage. The risk of liver damage with acetaminophen use is also increased by ingesting alcohol. Make sure you discuss with your doctor the maximum allowable dose of acetaminophen and any other guidelines for its use. Many people do not realize that acetaminophen is found in more than 600 over-the-counter drugs. It can be found in combination with other active ingredients in many cold, sinus, and cough medications. The cumulative effect of acetaminophen must be considered if you are talking multiple drugs which contain acetaminophen. How can acetaminophen damage the liver? Acetaminophen changes into metabolites which are eliminated from the body. By taking more than the recommended maximum daily dose of acetaminophen, more toxic metabolites are produced than can be eliminated. Narcotic Analgesics There are two types of narcotic analgesics: the opiates and the opioids (derivatives of opiates). Opiates are the alkaloids found in opium (a white liquid extract of unripe seeds of the poppy plant). Opioids are any medication which bind to opioid receptors in the central nervous system or gastointestinal tract. According to Wikipedia, there are four broad classes of opioids:

Endogenous opioid peptides (produced in the body: endorphins, dynorphins, enkephalins) Opium alkaloids (morphine, codeine, thebaine) Semi-synthetic opioids (heroin, oxycodone, hydrocodone, dihydrocodeine, hydromorphone, oxymorphone, nicomorphine) Fully synthetic opioids (pethidine or Demerol, methadone, fentanyl, propoxyphene, pentazocine, buprenorphine, butorphanol, tramadol, and more) Opioids are used in medicine as strong analgesics, for relief of severe or chronic pain. Interestingly, there is no upper limit for the dosage of opioids used to achieve pain relief, but the dose must be increased gradually to allow for the development of tolerance to adverse effects (for example, respiratory depression). According to eMedicine, "Some people with intense pain get such high doses that the same dose would be fatal if taken by someone who was not suffering from pain."

There have been debates over the addictive potential of opioids vs. the benefit of their analgesic properties for treating non-malignant chronic pain, such as chronic arthritis. Some experts believe opioids can be taken safely for years with minimal risk of addiction or toxic side effects. The enhanced quality of life which opioids may provide the patient must be considered. Side Effects / Adverse Reactions of Opioids: Common side effects and adverse reactions:

nausea vomiting drowsiness dry mouth miosis (contraction of the pupil) orthostatic hypotension (blood pressure lowers upon sudden standing) urinary retention constipation and/or fecal impaction Less common side effects and adverse reactions:

confusion hallucinations delirium hives itch hypothermia bradycardia (slow heart rate) tachycardia (rapid heart rate) raised intracranial pressure ureteric or biliary spasm muscle rigidity flushing Most severe side effects and adverse reactions:

respiratory depression fatal overdose More Information on Specific Analgesics

Acetaminophen (Tylenol) Codeine (Tylenol #2,3,4) Darvocet (Propoxyphene/Acetaminophen) Darvon (Propoxyphene) Duragesic (Fentanyl Patch) Hydromorphone (Palladone, Dilaudid) Morphine (MSContin, Oramorph) Oxycodone (OxyContin, Roxicodone) Percocet (Oxycodone/Acetaminophen) Percodan (Oxycodone/Aspirin) Talwin NX (Pentazocine/Naloxone)

Ultracet (Tramadol/Acetaminophen) Ultram (Tramadol) Vicodin (Hydrocodone/Acetaminophen)

Analgesics Analgesics are medications used to relieve pain without reducing the consciousness of the patient. They work by reducing the amount of pain felt and this is generally achieved by interfering with the way the pain message is transmitted by the nerves. Analgesics will not treat the cause of the pain but they will provide temporary relief from pain symptoms. There are three main categories of analgesics. The first is the opioid analgesics which are prescription only medicines that are very potent, being chemically related to morphine. The second is the non-opioid analgesics. Non-opioid analgesics work by affecting the prostaglandin system, which is the system within the body responsible for producing pain. This category includes non-steroidal anti-inflammatory drugs, or NSAIDs, such as Aspirin, ketoprofen and ibuprofen. The last category is adjuvant analgesics, which are medicines typically used for purposes other than pain relief. This includes some antidepressants that may also help to relieve pain in specific circumstances. It is the second of these three categories of analgesic that is the focus of this website. They are over-the-counter drugs that are can be safely used provided that the recommended dosage restrictions are observed. They are non-habit forming and have an effective ceiling, at which point the patient will derive no further benefit from increasing the dosage. Non-opioid analgesics act peripherally and not centrally like opioids that depress the central nervous system (CNS) and inhibit the brain's ability to feel pain. Non-opioid analgesics target the chemical substances released by the brain in response to injury that facilitate the transmission of the pain stimuli to the brain. The most prevalent of these chemical mediators is prostaglandin. Non-opioid NSAIDs are effective because they serve to block the release of prostaglandin at the peripheral nerve sites. Prostaglandins serve a variety of regulatory functions within the body. One of these functions is to assist the transmission of pain signals to the brain so that you are readily alerted that damage or dysfunction has occurred within the body. Other prostaglandin actions include the regulating body temperature, inflammation, the elasticity of blood vessels and the contraction of smooth muscle tissue. When damage occurs to the body, prostaglandins are formed from the unsaturated fatty acids released by damaged cells. Prostaglandins contain an enzyme called cyclooxygenase (COX). Prostaglandin synthetase amplifies the amount of pain experienced by serving as a pain activator. They increase the sensitivity of the nerves to pain impulses. By reducing the synthesis of prostaglandin the amount of pain stimuli sent to the brain is correspondingly reduced. Analgesics like paracetamol and codeine mostly affect the central nervous system (CNS) while NSAIDs like ibuprofen and aspirin are more effective near the actually site of the pain, exerting their analgesic effect in the periphery. Codeine works on the CNS as a

weak opiate agonist that inhibits pain signals so that less pain is felt. Codeine achieves this by binding with receptors at various sites in the CNS to alter the chemical process that stimulates pain signals. Paracetamol is a weak prostaglandin inhibitor that blocks prostaglandin biosynthesis in the CNS. NSAIDs like Aspirin, ibuprofen, diclofenac, and ketoprofen block the pain impulse at the source of the pain. They work by hindering the body's ability to biosynthesise prostaglandin by adhering to the cyclo-oxygenase (COX) that controls the amount of prostaglandin produced by the immune system. The special nerve endings that transmit the pain message are sensitised to prostaglandin so, by restricting its presence, the pain message is reduced. This weakens the physiological chemical process that results in the sensation of pain.

Analgesics
Analgesics are medicines used to relieve pain such as headaches, backaches, joint pain, sore muscles, menstrual cramps, and pain that results from surgery, injury, or illness. While these drugs do not treat whatever is causing the pain, they can provide enough relief to make people more comfortable and to allow them to carry out their daily routines. Among the most common analgesics are aspirin (acetylsalicylic acid), ibuprofen, naproxen sodium, and ketoprofen--all in the general category known as nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs relieve pain and also reduce inflammation. Another common analgesic, acetaminophen (Tylenol, Panadol), provides pain relief but does not reduce inflammation. For some types of serious, chronic pain narcotic analgesics (also called opioid analgesics) are used. Analgesics in this category include natural narcotics (derived from the opium poppy), such as morphine and codeine (morphine-3-methyl ether), and synthetic narcotics, such as propoxyphene (Darvon) and meperidine (Demerol). Salicylic acid, the compound from which the active ingredient in aspirin was first derived, was found in the bark of the willow tree (Salix alba) in 1763 by Reverend Edmund Stone of Chipping Norton, England. Earlier accounts indicate that the ancient Greek physician Hippocrates (c.460-c.377 B.C.) used willow leaves to reduce fever and relieve pain. During the 1800s various scientists extracted salicylic acid from willow bark and produced the compound synthetically. In 1897, German chemist Felix Hoffmann working at the Bayer division of I.G. Farber developed an improved method for synthesizing aspirin and it was first marketed in 1899. Today, Americans alone consume about 16,000 tons of aspirin tablets annually. Ibuprofen, a type of carboxylic acid (carboxylic acid is the agent that gives aspirin its anti- inflammatory action), was developed by British drug manufacturer and retailer Boots and Company in the 1960s. It has the advantages of being more effective than aspirin for treating certain kinds of pain while causing fewer stomach problems. . For some types of serious, chronic pain narcotic analgesics (also called opioid analgesics) are used. Analgesics in this category include natural narcotics (derived from the opium poppy), such as morphine and codeine (morphine-3-methyl

ether), and synthetic narcotics, such as propoxyphene (Darvon) and meperidine (Demerol). Pain is the body's signal that something is wrong. Pain can result from an injury, such as a broken bone, a burn or a sprain; from overuse of muscles (including muscle tension due to stress); from infections, such as sinus infections or meningitis; or from natural events, such as childbirth. Pain begins at the level of the cells. In response to injury or inflammation, cells release chemical messengers. These chemical messengers alert other specialized cells called pain receptors. The pain receptors send signals to the brain. The brain interprets the signals, and we perceive pain. Analgesics work by either blocking the signals that go to the brain or by interfering with the brain's interpretation of the signals. Determining the best pain reliever depends, in part, on the type of pain. The two main categories are acute pain and chronic pain. Acute pain is usually temporary and results from something specific, such as a surgery, injuries, or infections. Chronic pain is any pain that lasts more than three months and may disrupt daily life. Sometimes chronic pain is just a nagging discomfort, but it can flare up into severe pain. Although narcotic analgesics may be used, for most types of chronic pain a combination of non- narcotic medication and lifestyle changes is recommended. Overuse of pain relievers can actually make some types of pain worse. To manage long-term pain, such as recurring headaches, chronic backache, or arthritis pain, many pain treatment specialists recommend an approach that helps people cope without depending on large or frequent doses of drugs. Relaxation techniques, biofeedback, massage, exercise, proper diet, and good sleep habits can all be helpful. Caution is also recommended when exercising after taking an analgesic to relieve the pain of an injury. Since the analgesic depresses the body's pain signals, the injury can actually be aggravated by exercising when pain signals are muted. Side effects are one reason to be careful about frequent or long-term use of pain relievers. Narcotic analgesics are very effective, but can cause addiction. Aspirin and ibuprofen can irritate the stomach. Acetaminophen does not produce the side effects that aspirin and ibuprofen do, but high doses can cause liver damage, especially in people who drink alcohol regularly. Some pain relievers contain caffeine, which enhances their effectiveness. Taking these drugs near bedtime can interfere with sleep

Prescription Drugs Non-Prescription Drugs

Analgesics are medicines that relieve pain. Every type of pain killer medicine has its advantages and disadvantages. One medicine which is effective for a specific type of pain many not be effective for another kind. So such mdesicines need to be taken very carefully.

Purpose of Analgesics
Analgesics are prescribed to relieve pain of all sorts - headaches , backaches, joint pain, sore muscles, menstrual cramps and pain that results from surgery, injury or illness. While these drugs do not treat whatever is causing the pain, they can provide enough

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Throughout human history, people have sought ways to reduce pain. Until modern times, only a few effective Analgesics existed. But today, a wide range of pain relievers are available.

How Analgesics Work?

Pain is the body's signal that something is wrong. Pain can result from an injury, such as a broken bone, a burn or a sprain; from overuse of muscles (including muscle tension due to stress); from infections, such as sinus infections or Meningitis; or from natural events, such as child birth. Pain begins at the level of the cells. In response to injury or inflammation, cells release chemical messengers. These chemical messengers alert other specialized cells called Pain Receptors. The Pain Receptors send signals to the brain. The brain interprets the signals, and we perceive pain. Analgesics work by either blocking the signals that go to the brain or by interfering with the brain's interpretation of the signals.

Common Analgesics

Aspirin Choline Salicylate Magnesium Salicylate Sodium Salicylate Ibuprofen Naproxen Sodium Ketoprofen These are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs). NSAIDs relieve pain and also reduce inflammation. There is another common analgesic, Acetaminophen provides pain relief but does not

reduce inflammation.Determining the best pain reliever depends, in part, on the type of pain. The two main categories are acute pain and chronic pain.

ANALGESICS
(see Agonist/Antagonist Analgesics, Bromptons Cocktail, Heroin, Meperidine, Methadone, Morphine, Subcutaneous Infusions)

Continuous pain needs continuous pain relief. The cardinal rule is to give
regular analgesia to keep pain away. Never prescribe PRN. (In hospice medicine, PRN means Pain Relief Negligible.) Regular analgesia should ideally be oral, easy to take, and with few side effects, so that the patient can live as normal a life as possible once pain is controlled. There are three basic analgesics: Acetaminophen (non-opioid) Codeine (weak opioid) Morphine (strong opioid)

Other analgesics are alternatives to these. Mild pains need mild analgesics. Acetaminophen (1g every 4 hours) is an effective analgesic for mild pains. Moderate pains respond to weak opioid drugs such as codeine. If oral codeine 60mg every 4 hours does not abolish pain, the patient should be started on oral morphine. If weak opioids reduced the pain, it usually means that the pain is opioid-responsive, and will be well controlled on the correct dose of oral morphine. It is illogical and ineffective to try several drugs from the same group (morphine with another opioid drug). When weaker opioids prove ineffective, start oral morphine. The principle is to start with a low dose, and to titrate, increasing promptly in steps until the pain is controlled. The usual starting dose for 4-hourly oral morphine is 5mg. The dose may be increased every 4 hours in steps: 5mg, 10mg, 20mg, 30mg, 45mg, 60mg (or more as needed). Once the patients pain is well controlled on 4-hourly oral morphine, it is possible to stop the 4-hourly morphine and change to an equivalent dose of MS-Contin (morphine sulfate controlledrelease) every 12 hours. (Do not use 4 hourly oral morphine and MS-Contin together. It is unnecessary and tends to confuse both patient and carers.) If the patient is pain-free and drowsy, reduce the dose of morphine. The aim is to have a pain-free and alert patient. (see Morphine, Prescribing)

Never prescribe opioid agonist/antagonists (buprenorphine, nalbuphine, pentazocine) with opioid agonists (codeine, morphine). (see Agonist/Antagonist Analgesics) Always start a laxative and anti-emetic at the same time as morphine or any of the opioids, weak or strong. (see Constipation, Laxatives, Nausea & Vomiting) Polypharmacy in hospice and palliative care is unavoidable and necessary. However, fixed mixtures of drugs which have not been individually titrated should be avoided. (see Bromptons Cocktail, Prescribing)

There is no place in terminal care for patient-controlled analgesia. The aim is to

achieve total pain control with as simple a regime as possible, releasing the patient to think about more important things than pain. If the patient is unable to swallow (for example, due to dysphagia or vomiting), change to one of the following: Morphine suppositories Morphine by IM injection (for the short term only) Morphine by continuous subcutaneous infusion

Many analgesics are not suitable for management of chronic pain, and include: Dihydrocodeine (constipating) Pentazocine (dysphoriant effect) Meperidine (too short-acting) Methadone (too long-acting)

There is no known opioid superior to morphine. Pain that does not respond to
carefully titrated doses of morphine will not respond to other opioid analgesics. Other opioid analgesics should generally be avoided. (see Morphine) The table below is a guide to equi-analgesic oral doses. It is useful when changing a patient from regular oral analgesia with one of the other opioids to regular oral analgesia with morphine, in order to avoid prescribing too much morphine (drowsiness) or too little (pain breakthrough) at time of changeover. The table does not apply to single doses. CONVERSION TABLE FOR STRONG ORAL OPIOIDS Applies to Oral Use Only 4-hourly morphine Meperidine Pentazocine Methadone 50mg 50mg 5mg 5mg 5mg 20mg

Hydromorphone

5mg

25mg

Opioid is a term meaning any compound (natural or synthetic) which has morphine-like activity and which is antagonized by naloxone. No known opioid analgesic is superior to morphine, but since the elucidation of the structure of morphine in 1925, much effort has gone into producing new chemical entities with equal analgesic effect but without the sideeffects. Opioids act at receptors in the brain (especially the midbrain) and at the spinal cord to inhibit the transmission of pain. There are several different types of receptors. Most opioid drugs in clinical use (like morphine, codeine, methadone, and meperidine) act at the mu-receptors. They are selective mu-receptor agonists (causing strong analgesia but also other side effects). The structure of all these drugs (and the naloxone molecule) is similar, with a phenyl-N-methyl piperidine backbone which fits the mu-receptor. Some analgesics (pentazocine, for example) also stimulate sigma-receptors, causing dysphoria. If an opioid selective to kappa-receptor agonists could be developed there is some evidence that the result would be strong analgesia with fewer side-effects. Clinical differences between opioids concern: Analgesic ceiling Oral efficacy Speed of onset Duration of action Side-effects Potential for abuse

The potency of the drug (the amount in milligrams needed to achieve a given analgesic effect) is not as relevant as the analgesic ceiling (the highest strength of the drug which can be given in order to achieve the needed analgesic effect). Morphine has a high ceiling, so increasing the dose can increase the analgesic effect even at high doses. Agonist/antagonist drugs have a low ceiling. (see AgonistlAntagonist Analgesics) Oral efficacy depends on lipid solubility (rate of absorption) and susceptibility to first-pass metabolism in the liver. Methadone is well absorbed and slowly metabolized and therefore has a long half-life. More lipid-soluble drugs have a more rapid onset of action (crossing the blood-brain barrier more easily), but also leave the CNS more readily (and thus have a shorter duration of action). Duration of action also depends on receptor affinity. The duration of pain relief varies from about 1 to 2 hours (meperidine) to 4 hours (morphine) to 8 hours (buprenorphine, methadone).

Side-effects depend not only on the receptor profile of the drug, but also on the receptor profile of the patient, which explains, for example, why some patients develop severe nausea with buprenorphine or constipation with dihydrocodeine, and others do not. (If a patient cannot tolerate one opioid analgesic it is still worth trying another.) Physical dependence can occur with most opioids after 3 to 4 weeks in a person without pain, but does not occur in a patient with pain.

AGONIST/ANTAGONIST ANALGESICS
This group of drugs includes: Buprenorphine Pentazocine Nalbuphine

These are effective analgesics for moderate pain. Buprenorphine has a small place in the management of cancer pain, but the other drugs have no advantages over buprenorphine in this situation, and should be avoided. Buprenorphine is a strong narcotic, but has a low ceiling effect. It is rapidly metabolized by the liver, and (where available) the sublingual route allows systemic absorption which is almost as potent as by IM injection. About 20% of patients complain of unacceptable nausea or dizziness. All three drugs have two disadvantages. First, above a certain dose the incidence of side effects increases with no increase in analgesia (the ceiling effect). Second, their high affinity for morphine mu receptors (agonist action) blocks the effect of morphine (antagonist action).

Buprenorphine and morphine should never be given together. If buprenorphine

is given to a patient on morphine it can displace morphine from the receptor and cause pain (and sometimes withdrawal symptoms of yawning & sweating, rhinorrhea, nausea and restlessness).