CHAPTER ONE

INTRODUCTION

Chemistry and Therapeutic Effects of Analgesics is an effort to bring together various work (publications) on the chemistry of drugs with analgesic properties and their therapeutic effects.

It seeks to bring to the interest of a chemist, the import of application of specialize knowledge such as chemistry to preparing selected analgesics, showing latent potency of chemical knowledge in solving the problem of various types of pain and that with relatively lesser cost than that usually invested by pharmacologist in trying to understand the inroad to pain management.

The effectiveness of analgesics cannot be over-emphasized; hence this work to an extent reveals the broad world of analgesic and showed light on the chemistry of the treatment of pain.

What is an analgesic?    

An analgesic, known colloquially as a painkiller, is any natural or synthetic drug that relieves pain (produces analgesia) without causing loss of consciousness, paralysis, or other major impairment of sensory function or nerve impulse conduction. It is different from anesthetics, which produces anesthesia i.e. relives pain by causing loss of consciousness e.g. of such anesthetic is N₂O (Concise oxford dictionary, 2012).

The word analgesic derives from Greek an- (“without”) and -algia (“pain”). The term analgesia refers to an absence of the sensation of pain while still being conscious.                                                                                                                                                                                                                                                             An analgesic is any member of diverse group of drugs used to relieve pain. The type of analgesic used depends on the severity of pain; whether it is acute (self-limiting in duration, such as childbirth) or chronic (lasting more than three months) and the response to other medications (Uretsky 2002). However the World Health Organization’s “pain ladder,” originally developed for cancer-related pain, is a widely used protocol for determining in a stepwise manner the suitable drug and dosage for treating pain (WHO, 1990).

The choice of analgesia is also determined by the type of pain: for neuropathic pain, traditional analgesia is less effective, and there is often benefit from classes of drugs that are not normally considered analgesics, such as tricyclic antidepressants and anticonvulsants (Dworkin et al. 2003). Analgesic drugs act in various ways on the peripheral (PNS) and central nervous systems (CNS), either blocking the signal from the PNS or distorting the interpretation by the CNS (Uretsky 2002).

Medical researchers have developed widely diverse compounds for treating pain, including some synthetic opioids that produce an analgesic effect but that are much less likely to induce dependency. It is important to note that some pain is productive, acting as a warning of injury and a guide to diagnosis and treatment; thus it is also important to realize that while analgesics relieve symptoms, they do not affect the underlying cause (Uretsky 2002).

• EVIEW OF MAJOR CLASSIFICATIONS OF ANALGESICS

There are two major classifications of analgesics: Opioids or Narcotic analgesics andNonopioids analgesics.

What is an opiod?

A sample of raw opium

The term “opioid” originated in the 1950s. It combines “opium” + “-oid” meaning “opiate-like” (“opiates” being morphine and similar drugs derived from opium). The first scientific publication to use it, in 1963, included a footnote stating, “In this paper, the term, ‘opioid’, is used in the sense originally proposed by George H. Acheson (personal communication) to refer to any chemical compound with morphine-like activities”. By the late 1960s, research found that opiate effects are mediated by activation of specific molecular receptors in the nervous system, which were termed “opioid receptors”. The definition of “opioid” was later refined to refer to substances that have morphine-like activities that are mediated by the activation of opioid receptors. One modern pharmacology textbook states: “the term opioid applies to all agonists and antagonists with morphine-like activity, and also the naturally occurring and synthetic opioid peptides”.Another pharmacology reference eliminates the morphine-like requirement: “Opioid, a more modern term, is used to designate all substances, both natural and synthetic, that bind to opioid receptors (including antagonists)”. Some sources define the term opioid to exclude opiates, and others use opiate comprehensively instead of opioid, but opioid used inclusively, is considered modern, preferred and is in wide use (Offermanns and Stefan 2008).

Natural opioids occur in 2 places:

1. In the juice of the opium poppy (morphine and codeine)
2. As endogenous endorphins.

All other opioids are prepared from either morphine (semi synthetic opioids such as heroin) or they are synthesized from precursor compounds (synthetic opioids such fentanyl, hydrocodone, oxycodone).

The terms opiate and narcotic are sometimes encountered as synonyms for opioid. Opiate is properly limited to the natural alkaloids found in the resin of the opium poppy although some include semi-synthetic derivatives. Narcotic, derived from words meaning numbness or sleep, as an American legal term, refers to cocaineand opioids, and their source materials; it is also loosely applied to any illegal or controlled psychoactive drug. In other jurisdictions all controlled drugs are legally classified as narcotics. The term can have pejorative connotations and its use is generally discouraged where that is the case.

Opiods are primarily used for pain relief, including anesthesia they are also used to suppress cough, suppress diarrhea, treat addiction, reverse opioid overdose, and suppress opioid induced constipation. Extremely strong opioids are approved only for veterinary use such as immobilizing large mammals.

Opioids act by binding to opioid receptors, which are found principally in the central and peripheral nervous system and the gastrointestinal tract. These receptors mediate both the psychoactive and the somatic effects of opioids. Opioid drugs include partial agonists and antagonists, which produce moderate or no effect (respectively) but displace other opioids from binding in those receptors.

The Opioid Analgesics

Opioid analgesics, known also as “narcotic analgesics,” are analgesics derived from opium, as well as semi-synthetics and even synthetics that behave pharmacologically like morphine, and are pain relievers that act on the central nervous system (Uretsky 2002; Ross-Flanigan 2002). The archetypal opioid is morphine, a derivative of the opium poppy. The morphine molecule is the chemical basis of many painkillers, some with minimal abuse potential (Uretsky, 2002). In addition to morphine, other narcotic analgesics include codeine, oxycodone, propoxyphene (Darvon), hydrocodone, and diacetylmorphine (heroin, meperidine (Demerol), and pethidine). All exert a similar influence on the cerebral opioid receptor system. Tramadol and buprenorphine are thought to be partial agonists of the opioid receptors.

Opium is a narcotic formed from the latex (i.e., sap) released by lacerating (or “scoring”) the immature seed pods of opium poppies (Papaversomniferum). The opium latex contains up to 16 percent morphine, as well as codeine and non-narcotic alkaloids, such as papaverine and noscapine (Ross-Flanigan, 2002). Heroin (diacetylmorphine or diamorphine) is a semi-synthetic opioid synthesized from morphine. As with other opiates, heroin can act both as a painkiller and a recreational drug.

Codeine is an alkaloid found in opium. While it can be extracted from opium, most codeine is synthesized from morphine through the process of O-methylation. Codeine is by far the most widely used opiate in the world and very likely most commonly used drug overall.

Opioids, while very effective analgesics may have some unpleasant side-effects. Drowsiness, dizziness, and breathing problems are some unwanted side effects, as well as physical and mental dependence (Ross-Flanigan, 2002). Like all narcotics, opioids can become habit-forming. In addition, up to one in three patients starting morphine may experience nausea and vomiting (generally relieved by a short course of antiemetics). Pruritus (itching) may require switching to a different opioid. Constipation occurs in almost all patients on opioids, and laxatives (lactulose, macrogol-containing or co-danthramer) are typically co-prescribed.

Dosing of all opioids may be limited by opioid toxicity (confusion, respiratory depression, myoclonic jerks and pinpoint pupils), but there is no dose ceiling in patients who tolerate this.

When used appropriately, opioid analgesics are otherwise safe and effective. However, risks such as addiction and the body becoming used to the drug are serious concerns. Due to the body getting used to the drug, often the dose must be increased. If the drug is being used for treating a chronic disease, the doctor may follow the pattern of the no ceiling limit. What must be remembered, however, is that although there is no upper limit there is still a toxic dose even if the body has become used to lower doses. Frequent administration of heroin has a high potential for causing addiction and may quickly lead to tolerance. If a continual, sustained use of heroin for as little as three days is stopped abruptly, withdrawal symptoms can appear. This is much shorter than the withdrawal effects experienced from other common painkillers such as oxycodone and hydrocodone.

1.5 Other Classifications of Opiod

• Naturalopiates: alkaloids contained in the resin of the opium poppy, primarily morphine, codeine, and thebaine, butnot papaverine and noscapine which have a different mechanism of action; The following could be considered natural opiates: The leaves from Mitragynaspeciosa (also known as kratom) contain a few naturally-occurring opioids, active via Mu- and Delta receptors. Salvinorin A, found naturally in the Salvia divinorum plant, is a kappa-opioid receptor agonist.
• Esters of morphineopiates: slightly chemically altered but more natural than the semi-synthetics, as most are morphine prodrugs, diacetylmorphine (morphine diacetate; heroin), nicomorphine (morphinedinicotinate),dipropanoylmorphine (morphinedipropionate,desomorphine, acetylpropionylmorphine, dibenzoylmorphine, diacetyldihydromorphine.
• Semi-syntheticopioids: created from either the natural opiates or morphine esters, such as hydromorphone,hydrocodone, oxycodone, oxymorphone, ethylmorphine and buprenorphne;

• Fully syntheticopioids:

Suchas fentanyl, pethidine, levorphanol, methadone, tramadol and dextropropoxyphene;

• Endogenousopioid peptides, produced naturally in the body, such as endorphins, enkephalins, dynorphins, and endomorphins. Morphine, and some other opioids, which are produced in small amounts in the body are included in this category.

Tramadol and tapentadol, which act as monoamine uptake inhibitors also act as mild and potent agonists (respectively) of the μ-opioid receptor.Both drugs produce analgesia even when naloxone, an opioid antagonist, is administered.

Some minor opium alkaloids and various substances with opioid action are also found elsewhere, including molecules present in kratom, Corydalis, and Salvia divinorum plants and some species of poppy aside from Papaversomniferum. There are also strains which produce copious amounts of the baine, an important raw material for making many semi-synthetic and synthetic opioids. Of all of the more than 120 poppy species, only two produce morphine.

Amongst analgesics there are a small number of agents which act on the central nervous system but not on the opioid receptor system and therefore have none of the other (narcotic) qualities of opioids although they may produce euphoria by relieving pain—a euphoria that, because of the way it is produced, does not form the basis of habituation, physical dependence, or addiction. Foremost amongst these are nefopam, orphenadrine, and perhapsphenyltoloxamine and/or some other antihistamines. Tricyclic antidepressants have pain killing effect as well, but they’re thought to do so by indirectly activating the endogenous opioid system.

Other analgesics work peripherally (i.e., not on the brain or spinal cord). Research is starting to show that morphine and related drugs may indeed have peripheral effects as well, such as morphine gel working on burns. Recent investigations discovered opioid receptors on peripheral sensory neurons. A significant fraction (up to 60%) of opioid analgesia can be mediated by such peripheral opioid receptors, particularly in inflammatory conditions such as arthritis, traumatic or surgical pain.Inflammatory pain is also blunted by endogenous opioid peptides activating peripheral opioid receptors.

1.6 Opium Alkaloids

Many of the alkaloids and other derivatives of the opium poppy are not opioids or narcotics; the best example is the smooth-muscle relaxant papaverine. Noscapine is a marginal case as it does have CNS effects but not necessarily similar to morphine, and it is probably in a category all its own.
For the purpose of this study, a small list of few opium alkaloid is made. Though Phenanthrene is naturally occurring in (opium):

• Codeine
• Morphine
• Thebaine
• Oripavine

The side effects of opioids may include itchiness, sedation, nausea, respiratory depression, constipation, and euphoria although these side effects will be treated later in details. Tolerance and dependence also develop with continuous use, requiring increasing doses and leading to a withdrawal syndrome upon abrupt discontinuation. The euphoria attracts recreational use, and frequent, escalating recreational use of opioids typically results in addiction. Accidental overdose or concurrent use with other depressant drugs commonly results in death from respiratory depression. Because of opioid drugs’ reputation for addiction and fatal overdose, most are highly controlled substances (World Drug Report, 2015).Illicit production, smuggling, and addiction to opioids prompted treaties, laws and policing which have realized limited success. In 2013 between 28 and 38 million people used opioids illicitly (0.6% to 0.8% of the global population between the ages of 15 and 65). 2011 an estimated 4 million people in the United States used opioids recreationally or were dependent on them. Current increased rates of recreational use and addiction are attributed to over-prescription of opioid medications and inexpensive illicit heroin. Conversely, fears about over-prescribing, exaggerated side effects and addiction from opioids are similarly blamed for under-treatment of pain.

Non-clinical use was criminalized in the U.S by the Harrison Narcotics Tax Act of 1914, and by other laws worldwide. Since then, nearly all non-clinical use of opioids has been rated zero on the scale of approval of nearly every social institution. However, in United Kingdom the 1926 report of the Departmental Committee on Morphine and Heroin Addiction under the Chairmanship of the President of the Royal College of Physicians reasserted medical control and established the “British system” of control—which lasted until the 1960s; in the U.S. the Controlled Substances Act of 1970 markedly relaxed the harshness of the Harrison Act.

Before the twentieth century, institutional approval was often higher, even in Europe and America. In some cultures, approval of opioids was significantly higher than approval of alcohol. Opiates were used to treat depression and anxiety until the mid-1950s

Nonopiod or non narcotic

The two main classes of nonopioids are the nonsteroidal anti-inflammatory drugs (NSAIDs), including the salicylates, and acetaminophen (paracetamol).The NSAIDs also have antipyretic and anti-inflammatory effects; they reduce fever and inflammation. Acetaminophen is a non-narcotic analgesic that lacks anti-inflammatory effects.

The NSAIDs

NSAIDs are analgesics with antipyretic and anti-inflammatory effects. The term “non-steroidal” is used to distinguish these drugs from steroids, which (among a broad range of other effects) have a similar eicosanoid-depressing, anti-inflammatory action. The most prominent members of this group of drugs are aspirin, ibuprofen, and naproxen partly because they are available over-the-counter in many areas.

Aspirin and the other NSAIDs inhibit cyclooxygenase, leading to a decrease in prostaglandin production; this reduces pain and also inflammation (in contrast to acetaminophen and the opioids).

Beginning in 1829, with the isolation of salicin from the folk remedy willow bark, NSAIDs have become an important part of the pharmaceutical treatment of pain (at low doses) and inflammation (at higher doses). Part of the popularity of NSAIDs is that, unlike opioids, they do not produce sedation or respiratory depression and have a very low addiction rate. NSAIDs, however, are not without their own problems. NSAIDs predispose to peptic ulcers, renal failure, and allergic reactions.

Certain NSAIDs, including ibuprofen and aspirin, have become accepted as relatively safe and are available over-the-counter without prescription. The use of certain NSAIDs in children under 16, suffering from viral illness may contribute to Reye’s syndrome.

COX-2 inhibitors

These drugs have been derived from NSAIDs. The cyclooxygenase enzyme inhibited by NSAIDs was discovered to have at least two different versions: COX1 and COX2. Research suggested that most of the adverse effects of NSAIDs were mediated by blocking the COX1 (constitutive) enzyme, with the analgesic effects being mediated by the COX2 (inducible) enzyme. The COX2 inhibitors were thus developed to inhibit only the COX2 enzyme (traditional NSAIDs block both versions in general). These drugs (such as rofecoxib and celecoxib) are equally effective analgesics when compared with NSAIDs, but cause less gastrointestinal hemorrhage in particular. However, post-launch data indicated increased risk of cardiac and cerebrovascular events with these drugs due to an increased likelihood of clotting in the blood due to a decrease in the production of protoglandin around the platelets causing less clotting factor to be released, and rofecoxib was subsequently withdrawn from the market. The role for this class of drug is hotly debated. Illnesses inadvertently caused by doctors and medical treatments, called iatrogenic diseases, are possible when the treatment affects the patient’s blood, respiration, digestive processes and other bodily functions and organs.

From studies, it’s been shown there’s great need for newer NSAIDs. Reasons for this has been clearly pointed out in 2002 in a publication Newer Non-steroidal Anti-inflammatory Drugs – A Review of their Therapeutic Potential and Adverse Drug Reactions by Dhikav, Singh and Anand.

1.9 THE ACETAMINOPHEN

Acetaminophen or paracetamol (International Nonproprietary Name) is a popular analgesic and antipyretic (fever-reducing) drug that is used for the relief of headaches, fever, and minor aches and pains, such as pain in joints and muscles (The American Society of Health-System Pharmacists). Paracetamol is predominantly a centrally acting analgesic (non-narcotic) which mediates its effect by action on descending serotoninergic (5-hydroxy triptaminergic) pathways, to increase 5-HT release (which inhibits release of pain mediators). It also decreases cyclo-oxygenase activity. It has recently been discovered that most or all the therapeutic efficacy of paracetamol is due to a metabolite AM404, making paracetamol a prodrug) which enhances the release of serotonin and also interacts with the cannabinoid receptors by inhibiting the uptake of an andamide.

Acetaminophen or paracetamolis a major ingredient in numerous cold and flu medications and many prescription analgesics. When used responsibly in standard doses, it is considered effective and safe, but because of its wide availability and narrow therapeutic index, accidental or deliberate overdoses are not uncommon. Excessive doses lead to hepatotoxicity (liver damage) (Guideline 106: Control of pain in adults with cancer, 2008).

Other Analgesic Agents

In patients with chronic or neuropathic pain, various other substances may have analgesic properties, but are not typically classified as analgesics. Tricyclic antidepressants, especially amitriptyline, have been shown to improve pain in what appears to be a central manner. The exact mechanism of carbamazepine, gabapentin, and pregabalin is similarly unclear, but these anticonvulsants are used to treat neuropathic pain with modest success.

Mechanism of Action and Effects of Nonopioid Analgesic

The primary mechanism of action of NSAIDs is inhibition of the enzyme cyclooxygenase (COX), resulting in blockade of prostaglandin synthesis. Acetaminophen, another nonopioid, appears to act mostly via a central mechanism. All nonopioids have anti-inflammatory, antipyretic, and analgesic effects, but the anti-inflammatory effect of acetaminophen is essentially negligible. The analgesic effect of NSAIDs is prompt (minutes to hours), whereas the anti-inflammatory effect may take longer (1-2 weeks or longer). This latter effect can indirectly relieve some pain by reducing tissue swelling. The relatively recent discovery that COX has at least two isoforms, COX-1 and COX-2, has advanced NSAID pharmacology. COX-1 is constitutively expressed in most normal tissues, but plays an especially important role in the gastrointestinal (GI) tract, kidneys, and platelets; COX-1 primarily produces prostaglandins with beneficial effects (e.g., regulation of blood flow to the gastric mucosa and kidneys). In contrast, COX-2 is normally not present but may be induced in response to inflammatory stimuli; COX-2 primarily produces prostaglandins that activate and sensitize nociceptors. Nonselective NSAIDs inhibit COX-1 and COX-2, which contributes to both their therapeutic actions and side effects. Agents that selectively inhibit COX-2 were introduced to minimize the risk of GI side effects without compromising analgesic efficacy. The “coxibs” affect COX-2 both centrally and peripherally.

However, an increased risk of myocardial infarction, stroke, and death has been linked to selective COX-2 inhibitors, and this increased risk of cardiovascular side effects appears to be a class effect of NSAIDs, including nonselective agents. Rofecoxib and valdecoxib were voluntarily withdrawn from the market in 2004 and 2005, respectively, because of these cardiovascular safety concerns. Celecoxib is still available because its benefits appear to outweigh its potential risks in certain patients. A third COX isoform, COX-3, recently was identified. There is evidence that inhibition of COX-3 represents the primary central mechanism by which acetaminophen relieves pain.

Other classification of Nonopioids Analgesic with examples includes:

1. Based on chemical nature-
2. Non-Selective COX Inhibitors-Salicylic acid derivatives e.g. Aspirin, Sodium salicylate.
   1. Para-amino phenol derivatives e.g. Acetaminophen.
   2. Indol and Indane acetic acids e.g. Indomethacin, Sulindac.
   3. Heteroaryl acetic acids e.g. Tolmetin, Diclofenac, Keterolac.
   4. Aryl propionic acids e.g. Ibuprofen, Naproxen, Flurbiprofen, Ketoprofen, Fenoprofen, Oxaprofen.
   5. Anthranilic acids e.g. Mefenamic acid, Meclofenamic acid.
   6. Enolic acids (Oxicams) e.g. Piroxicam, Meloxicam, Tenoxicam, Isoxicam.
   7. Alkanones e.g. Nabumetone.

• Selective COX-2 Inhibitors
  1. Indole acetic acids e.g. Etodolac.
  2. Sulfonanilides e.g. Nimesulide.
  3. Diaryl substituted furanones e.g. Rofecoxib.
  4. Diaryl substituted pyrazoles e.g. Celecoxib.

1. Based on mode of inhibition of COX-
2. Class I: Simple, competitive reversible inhibition that competes with arachidonic acid for binding to the COX site e.g. Ibuprofen, Piroxicam, Sulindac, Meclofenamic acid and Naproxen.
3. Class II: Competitive, time dependent reversible inhibitors that bind to the COX active site in the first phase to form reversible enzyme inhibitor complex e.g. Flurbiprofen, Diclofenac

• Class III: Competitive, time dependent, irreversible inhibitors that form an enzyme inhibitor complex e.g. Aspirin.
• On the basis of selective inhibition of COX
  1. Selective COX inhibitors
  2. Salicylates Acetylated: Aspirin.

1. Non acetylated: Salsalate, Trisalycilate.
2. (2) Non selective COX-1/COX-2 or Traditional NSAIDs: Ibuprofen, Indomethacin, Neproxen, Silindac, Ketoprofen, Ketorolac, Fenoprofen, Diclofenac, Piroxicam, Oxaprazine.t.c.
3. (3) Semi selective NSAIDs: Meloxicam, Etodolac, Nabumatone.

• (4) COX-2 selective Inhibitor: Celecoxib, Rofecoxib, Enterocoxib.

Specific Forms and Uses of Analgesics

Combinations: Analgesics are frequently used in combination, such as the acetaminophen and codeine preparations found in many non-prescription pain relievers. Propoxyphene and acetaminophen are used together (Darvocet N), as are oxydodone and acetaminophen (Percocet, Roxicet), and hydrocodone and acetaminophen (Lortab, Anexsia) (Ross-Flanigan 2002). Analgesics also can be found in combination with vasoconstrictor drugs such as pseudoephedrine for sinus-related preparations, or with antihistamine drugs for allergy sufferers.

The use of acetaminophen (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 that 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 be prescribed together (Mehlisch, 2002).

Topical or systemic Analgesics: 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, an anesthetic, 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.

Psychotropic agents: Tetrahydrocannabinol (THC) and some other cannabinoids, either from the Cannabis sativa plant or synthetic, have analgesic properties, although the use of cannabis derivatives is illegal in many countries. Other psychotropic analgesic agents include ketamine (an NMDA receptor antagonist), clonidine and other α₂-adrenoreceptor agonists, and mexiletine and other local anaesthetic analogues.

A typical and/or adjuvant analgesics: Orphenadrine, cyclobenzaprine, scopolamine, atropine, gabapentin, first-generation antidepressants, and other drugs possessing anticholinergic and/or antispasmodic properties are used in many cases along with analgesics to potentiate centrally acting analgesics such as opioids when used against pain especially of neuropathic origin and to modulate the effects of many other types of analgesics by action in the parasympathetic nervous system. Dextromethorphan has been noted to slow the development of tolerance to opioids and exert additional analgesia by acting upon the NMDA receptors; some analgesics such as methadone and ketobemidone and perhaps piritramide have intrinsic NMDA action.

The use of adjuvant analgesics is an important and growing part of the pain-control field and new discoveries are made practically every year. Many of these drugs combat the side effects of opioid analgesics—an added bonus. For example, antihistamines, including orphenadrine, combat the release of histamine caused by many opioids; methylphenidate, caffeine, ephedrine, dextroamphetamine, and cocaine and work against heavy sedation and may elevate mood in distressed patients as do the antidepressants.

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