ANALGESICS Pain Management

What is pain? – A protective mechanism to inform of damage or the presence of disease – Part of the normal healing process

ANALGESICS I. (narcotic) analgesics 1. of opioid receptors – hydrochloride, promedol , , ; 2. Agonists – antagonists and partial agonists of opioid receptors – pentazocin, . II. Non-opioid analgesics and non steroidal anti- inflammatory - NSAIDs acetylsalicylic acid, paracetamol, analgin, indomethacin, butadion, ibuprofen, pyroxicam, diclofenac-sodium, ketorolac, ketoprofen. III. Substances with mixed mechanism of action (opioid and non-oioid components) tramadole Classification of Pain By Onset and Duration Acute pain  Sudden in onset  Usually subsides once treated

Chronic pain  Persistent or recurring  Often difficult to treat Major Sources of Pain

Source Area Involved Characteristics Treatment

Somatic body throbbing, narcotics, framework stabbing NSAIDS

Visceral kidneys, aching, narcotics, intestines, throbbing, NSAIDS liver sharp, crampy

Neuropathic Nerves burning, narcotics, numbing, NSAIDS, tingling antidepressants, anticonvulsants OPIOID ANALGESICS History of

• is extracted from poppy seeds (Papaver somniforum) • Used for thousands of years to produce: – Euphoria – Analgesia – Sedation – Relief from diarrhea – Cough suppression Morpheus is the Greek god of dreams and sleep.

Friedrich Wilhelm Adam Sertürner, a German pharmacist, isolated Morphine from opium, in 1805. Opioid receptors • group of G-protein coupled receptors with opioids as ligands. • The endogenous opioids are dynorphins, enkephalins, endorphins, endomorphins and .

Subtypes of opiod receptors: mu, delta, kappa, epsilon, sigma

Opiod Receptor Activation

Response Mu-1 Mu-2 Kappa Delta Sigma

Analgesia

Respiratory depression Euphoria

Dysphoria

Decrease GI motility Physical Dependence Mania, hallucination Applications in Dentistry

• Narcotic (opioid) analgesics are extremely effective in reducing acute dental and postoperative pain. • The narcotic analgesics have established for the treatment of pain in those situations where the NSAIDs are less effective. • , , codeine, and occasionally meperidine are the narcotics used to treat dental pain. Opioid Analgesics

• Opioid analgesics are well known for their ability to reduce the perception of pain without a loss of consciousness. • Opium contains morphine, codeine,noscapine, papaverine, and . • Thebaine is a convulsant that produces no analgesia, and as such it is not used clinically. • Opium is a less effective than pure morphine, because it is slowly absorbed, and has been historically used for its constipating action. • Morphine itself, has a variety of effects, among which are an increase in the tolerance to pain, euphoria, an antitussive effect, respiratory depression, constipation and emesis. In addition, morphine has a high addiction liability. • Derivatives of morphine have been sought that retain the analgesic activity of the parent, but that have improved oral bioavailability and a reduction in addiction liability and other harmful side effects. • The structure of morphine is shown below. The rings are lettered A (aromatic), B (cyclohexane), C (cyclohexene), D (piperidine) and E (tetrahydrofuran). All of the derivatives of morphine which possess this basic ring structure have a high addiction liability which is roportional to their analgesic activity. • Structure/Activity Relationships of Morphine Analogues: • Modifications at the 3- and 6-hydroxyl groups: • · Conversion of the 3-OH to a 3-OCH3, yielding codeine, reduces activity to 15% of morphine. Groups larger than a methoxy reduce activity dramatically. • · Conversion of the 6-OH to a 6-OCH3, yielding heterocodeine,results in a six-fold increase in activity. • Oxidation of the 6-OH to a ketone reduces activity when the 7,8-double bond is present (morphinone = 37% of morphine). • However, as shown below, when the 7,8-double bond is saturated, a 6-keto will increase activity.

• · Removal of the 6-OH (6-desoxymorphine) increases activity 10-fold in the dihydro series. • · Acetylation of both the 3- and 6-OH produces 3,6-diacetylmorphine,also known as . Heroin is 2-3 times more potent than morphine. • Most of this increase is due to increased lipid solubility, which leads to enhanced and rapid CNS penetration.

• Modifications at the 7,8-double bond: • Reduction of the 7,8-double bond results in a slight increase in activity, as in and .

• As mentioned above, saturation of the 7,8-double bond has the greatest effect when combined with modifications at the 6-position (as in dihydromorphinone and dihydrocodinone). C6=O • Modifications of the nitrogen substituent: • Methyl is the optimal substituent for activity, and ethyl is okay. • If the nitrogen substituent is a hydrogen, analgesic effect is reduced 75%, and addiction liability is lowered. • Addition of a phenethyl substituent in place of methyl results in a 14-fold increase in activity over morphine. • Quaternary ammonium derivatives such as N,N- dimethyl-morphine have no analgesic activity, but do have significant curare-like activity. • • If the nitrogen substituent is a bulky alkyl group such as propyl, isobutyl, or especially allyl and cyclopropylmethyl, the compound becomes a narcotic antagonist. • Nuclear (ring) substitutions: • Opening up the ether linkage (E ring) to form the catechol-type ring system (3-OH and 4-OH) will reduce activity by 90% less than morphine.

• Addition of a 14-beta-OH results in a dramatic increase in activity in the dihydromorphinone series.

• · If the 6 position is substituted with a methylene substituent, as in the structure above (6- methylene-dihydromorphine), the resulting analogue has 80 times the potency of morphine. Representative Morphine Analogues • Tylox contains a combination of acetaminophen and oxycodone. Oxycodone is an opioid pain medication. An opioid is sometimes called a narcotic. Acetaminophen is a less potent pain reliever that increases the effects of oxycodone. Treatment of acute poisoning

 Naloxon (antagonist of opioid receptors) intravenously - 0,4-1,2 mg general dose of naloxon should not overcome 10 mg  stomach lavage (for morphine enterohepatic circulation is typical) with 0,05-0,1% solution of potassium permanganate and 0,5 % tannin solution  suspension of 20-30 g of activated charcoal  salt laxative agents (sodium sulfate)  forced diuresis  atropine sulfate

 inhalation of carbogen (5-7 % СО2 and 93-95 % O2) There are two agents in the morphine class which are marketed as morphine antagonists. These agents, and , are shown below. Naloxone is a pure antagonist, and is commonly used to treat narcotic overdose. Naltrexone is a similar agent, but does possess weak agonist activity, and is used to treat former narcotic addicts. Structure/Activity Relationships of The morphinans, which were first intruduced by Grewe in 1946, are similar in structure to the morphine analogues, but lack the E ring found in the naturally occurring opioids, as well as the 6-OH and the 7,8-double bond. Their general structure is represented by , which is shown below. The structure/activity relationships of the morphinans are very similar to those of the : 1- A 3-OH is optimal, and a 3-methoxy is less active. 2-The nitrogen substituent produces the same activity as in the morphines. 3-No other substituents may be added to the A ring. 4- The C ring must be unsubstituted.

Levallorphan. (INN, BAN) (brand names Lorfan, Naloxifan, Naloxiphan), also known aslevallorphan tartrate (USAN), is an opioid modulator of the family used as an opioid analgesic and /antidote.

Butorphanol is an opioid pain medication. An opioid is sometimes called a narcotic. is used to treat moderate to severe pain. It is also used as part of anesthesia for surgery, or during early labor (if childbirth is expected to be more than 4 hours away). Structure/Activity Relationships of Benzomorphans The benzomorphans, which were first introduced by May in 1960, are also similar in structure to the morphine analogues, but lack the C and E rings found in the naturally occurring opioids. Their general structure is shown below. The structure/activity relationships of the follow the same pattern as the morphinans: 1-The nitrogen substituent (R3) follows the same rules as the morphinans and morphines. However, antagonist substituents produce analogues with a higher agonist/antagonist ratio. 2- R1 and R2 substituents must be present to supply vestiges of the C ring. These are usually methyl, or a similar lower alkyl. R2 must be alpha for the analogue to have agonist activity. R1 can be alpha (cis), producing analogues with activity about equal to morphine, or beta (trans), producing agents 4-30 times as active as morphine. The beta agents will support narcotic addiction, while the alpha series will not. 3-R4 must be OH or methoxy. , sold under the brand name Talwin among others, is a painkiller used to treat moderate to severe pain. It is believed to work by activating κ-opioid receptors and blocking μ-opioid receptors. Structure/Activity Relationships of the 4-Phenylpiperidines

The representitive 4-phenylpiperidine, meperidine (Demerol, below) was first prepared as an antispasmodic, and in addition to this activity it was found to be analgesic at about 20% the potency of morphine. Note that the compound follows the morphine rule. , also known as meperidine and sold under the brand name Demerol among others, is a synthetic opioid pain medication of the phenylpiperidine class. Synthesized in 1939 as a potential agent by the German chemist Otto Eisleb, its analgesic properties were first recognized by Otto Schaumann ... The structure/activity relationships of 4-phenylpiperidines are fairly simple: 1- Both esters and reverse esters at the 4 position are active, as are the simple ketones. propyl is the optimal chain length (excluding the ester oxygen). • The phenyl ring at the 4 position is necessary for activity, and must be able to assume the axial position, as shown above. Addition of a m-OH group will enhance activity; such analogues are called bemidones. • If a reverse ester is combined with a 3-methyl, the analogues are known as (see below). The methyl group may cause enantiomeric recognition by the .

The nitrogen substituent is a methyl in most cases. A phenethyl or its equivalent will increase activity. It is not possible to confer antagonist activity with a nitrogen substituent such as allyl. Representative 4-Phenylpiperidines The initial adult dosage is 2 Lomotil tablets four times daily (maximum total daily dose of 20 mg per day of hydrochloride). Most patients will require this dosage until initial control of diarrhea has been achieved. Clinical improvement of acute diarrhea is usually observed within 48 hours.

Fentanyl, also known as fentanil, is an opioid which is used as a pain medication and together with other medications for anesthesia.[2] It has a rapid onset and effects generally last less than an hour or two.[2] Fentanyl is available in a number of forms including by injection, as a skin patch, and to be absorbed through the tissues inside the mouth.[2] Open Chain Opioid Analgesics

Open chain analogues which follow the morphine rule can also have significant analgesic activity. The general structure of these analogues appears below: • Both phenyl groups must be present. • The nitrogen substituent R2 can vary, but the nitrogen should be tertiary. It is not possible to produce an antagonist in this class. • A m-OH reduces activity. • The (-)-isomers are most potent. • R1 is usually propionyl. C3H5O • R3 is usually methyl, and the total aliphatic chain length is usually 7 carbons. accumulates in lipid tissue outside of the CNS, and thus has a slow onset and long duration (24 hours). It is used for long term maintenence of addiction. Propoxyphene is a mild analgesic with a low addiction liability.

Methadone is an opioid medication. An Propoxyphene is in a opioid is sometimes called a narcotic. group of drugs called Methadone reduces withdrawal narcotic pain relievers. symptoms in people addicted to heroin or Propoxyphene is used to other narcotic drugs without causing the relieve mild to moderate "high" associated with the drug addiction. pain. Methadone is used as a pain reliever and as part of drug addiction detoxification and maintenance programs. It is available only from a certified pharmacy. Substances with mixed mechanism of action (opioid and non-oioid components)

(-)-trans-2-(Dimethylaminomethyl)-1-(m- methoxyphenyl)cyclohexanol hydrochloride is a centrally acting synthetic analgesic. Tramadol is not considered a narcotic although it is similar to morphine and there have been reports of dependence and addiction.

(+/-)-Tramadol is a selective agonist of mu receptors and preferentially inhibits serotonin reuptake, whereas (-)- tramadol mainly inhibits noradrenaline reuptake. The action of these 2 enantiomers is both complementary and synergistic and results in the analgesic effect of (+/-)- tramadol.

Tramadol, sold under the brand name Ultram among others,[2] is an opioid pain medication used to treat moderate to moderately severe pain.[1] When taken by mouth in an immediate-release formulation, the onset of pain relief usually occurs within an hour.[6] It is often combined with paracetamol (acetaminophen) as this is known to improve the efficacy of tramadol in relieving pain.[3] Desmetramadol is considerably more potent as a μ-opioid agonist compared to tramadol.[4] It also shows comparatively far lower affinity for the δ- and κ-opioid receptors.[5] The two enantiomers of desmetramadol show quite distinct pharmacological profiles;[6] both (+) and (−)-desmetramadol are inactive as serotonin reuptake inhibitors,[7] but (−)-desmetramadol retains activity as a norepinephrine ,[8] and so the mix of both the parent compound and metabolites contributes significantly to the complex pharmacological profile of tramadol. While the multiple receptor targets can be beneficial in the treatment of pain (especially complex pain syndromes such as neuropathic pain), it increases the potential for drug interactions compared to other opioids, and may also contribute to side effects. NON-OPIOID ANALGESICS Pharmacodynamic Effects

• Analgesic • Antipyretic • Anti-inflammatory (except paracetamol) NSAIDs including aspirin and acetaminophen, two of the oldest pain medications, are among the most widely prescribed drugs worldwide for the treatment of rheumatic Arthritis and other degenerative inflammatory joint diseases. Although NSAIDs are very effective in relieving mild to moderate pains and inflammation, their use is also often associated with many undesirable side effects, including GI irritation and bleeding, platelet dysfunction, kidney damage, and bronchospasm. With the exception of acetaminophen (Tylenol) and the newer “coxibs” drugs, the conventional NSAIDs (also commonly referred to as the aspirin-like drugs),share very similar therapeutic and side effect profiles. The conventional NSAIDs exert their therapeutic action by inhibiting two isoforms of cyclooxygenase (COX-1, the constitutive isozyme and COX-2, the inducible isozyme), which is the rate-limiting enzyme responsible for the biosynthesis of the proinflammatory prostaglandins (PGs) such as the PGD2 , PGE2 ,PGF2œ, and PGI2 and thereby modulating pain transmission,attenuating inflammation and reducing fever They also produce their undesirable side effects such as GI bleeding, ulcerations, or renal impairments by blocking the same cyclooxygenases responsible for synthesizing PGs that modulate platelet activity (TXA2 and PGI2), gastric acid secretion and cytoprotection (PGE2 and PGI2 ), and renal blood flow (PGE 2 ). In early 1990, Vane et al. hypothesized that the undesirable side effects of the conventional NSAIDs are a result of inhibition of the COX-1 isozyme, whereas the therapeutic effects are related mainly to their inhibitory action on the inducible COX-2 isozyme.

This hypothesis has stimulated extensive drug development and hasty market introductions of many selective COX-2 inhibitors, or coxibs drugs. However, all of the marketed coxibs drugs except celecoxib (Celebrex), the first FDA-approved COX-2 drug in 1998, have been withdrawn from the market because of the potential risk of a cardiovascular event, including heart attack or stroke, especially in cardiac patients.

Recent clinical trials have placed all NSAIDs under surveillance for their potential cardiovascular risk, thus the indiscriminate use of any NSAIDs including naproxen in cardiac patients should be avoided. Mechanism of action of non-opioid analgesics

• depression of cyclooxygenases activity • decreasing of prostaglandins synthesis in peripheral tissues and in central nervous system • decreasing of sensitivity of nervous endings and depression of transmission of nociceptive impulses on the level of CNS structures • pain-relieving action of non-opioid analgesics is partly connected with their anti-inflammatory activity PGs from arachidonic acid (AA)

a polyunsaturated fatty acid released from membrane phospholipids by the action of phospholipase A2, Cyclooxygenase (also known as prostaglandin endoperoxide synthase or PGH synthase) is the rate-limiting enzyme responsible for the biosynthesis of PGs.

PGs are short-lived, lipidlike molecules that play a vital role in modulating many important physiological and pathophysiological functions including pain, inflammation, gastric acid secretion, wound healing, and renal function. They are biosynthesized via a tissue-specific cyclooxygenase pathway (COX-1 or COX-2) either on an as-needed basis (mostly via the COX-1 isozyme) or via the induced and overexpressed COX-2 isozyme because of an injury, inflammation, or infection.

Inhibition of PGE synthesis by the conventional NSAIDs in the parietal cells removes its ability to modulate histamine-mediated release of gastric acid from the parietal cells, whereas blockade of PGI2 and PGE2 synthesis in the epithelial cells in the stomach linings also prevents their action on the biosynthesis and release of bicarbonate and mucous gel desperately needed to repair damage resulting from erosion caused by gastric acid and other aggressive factors.Thus, it should not be surprising to note that NSAID- induced gastric ulcers can only be prevented clinically with coadministration of misoprostol, a stable PGE analog, but not with either the histamine H –antagonists, sucralfate, or any proton pump inhibitors such as omeprazole.

Effects of COX Inhibition by Most NSAIDS

COX-1 COX-2

Gastric ulcers Reduce inflammation

Bleeding Reduce pain

Acute renal failure Reduce fever

NSAIDs : anti-platelet—decreases ability of blood to clot Indications for administration of non- narcotic analgesics

 headache  toothache  backache  neuralgias  pulled muscles  joint pain  dysmenorrhea for potentiating of their action – combinations paracetamol with codeine, metamizol with dimedrol, metamizol with codeine Applications in Dentistry

• Toothache • Post extraction pain • Periodontitis • Neuritis • Stomatitis • Arthritis • Local usage as keratoplatic agents for hyperkeratosis, hyperesthesia Paracetamol (Acetaminophen)

• analgesic and antipyretic drug • maximal effect if the drug is introduced orally – after 2 hours, lasts approximately for 4 hours • in case of durable administration of big doses – damaging of liver and kidneys, production of met-hemoglobin Paracetamol (Acetaminophen) N-Acetyl-P-Aminophenol

Classification: analgesic, antipyretic, misc. not an NSAID

Mechanism: inhibits prostaglandin synthesis via CNS inhibition of COX (not peripheral)- doesn’t promote ulcers, bleeding or renal failure; peripherally blocks generation of pain impulses, inhibits hypothalamic heat-regulation center Paracetamol

• Tablets • Suppositories • Syrups • Soluble tablets • Capsules PARACETAMOL Pharmacokinetics: paracetamol

Metabolism: major and minor pathways Half-life: 1-3 hours Time to peak concentration: 10-60 min

Treatment for overdose: Acetylcysteine Paracetamol Liver Metabolism

1. Major pathway —Majority of drug is metabolized to produce a non-toxic metabolite 2. Minor pathway —Produces a highly reactive intermediate (acetylimidoquinone) that conjugates with glutathione and is inactivated.

• At toxic paracetamol levels, minor pathway metabolism cannot keep up (liver’s supply of glutathione is limited), causing an increase in the reactive intermediate which leads to hepatic toxicity and necrosis Acetylsalicylic acid  Blocks irreversibly COX  As antipyretic and analgesic drug – 0,25 and 0,5 g per time  As an anti-inflammatory – 3-4 g per day (for arthritis, myocarditis, pleuritis, bronchitis etc.  As platelets inhibitor - for prophylaxis of thrombus- formation (in case of ischemic heart disease, thrombophlebitis etc.) – daily dose – 80-100 mg Pharmacokinetics: ASA

Absorption: from stomach and intestine Distribution: readily, into most fluids/tissues Metabolism : primarily hepatic • ASA contraindicated for use in children with viral fever –can lead to Reye’s Syndrome • Fatal overdose is possible

Similar pharmacokinetics for ibuprofen and related NSAIDs Analgin (metamizol-sodium) Baralgin (maxigan, spazgan, spazmalgon, trigan) metamizol-sodium +pitophenon hydrochloride+pheniverinium bromide Ampoules tablets suppositories

Analgesic and spasmolytic activity Traditional and selective COX-2 inhibitors

Ketorolak (ketanov)

• according to analgesic activity it prevails over effect of acetylsalicylic acid, indometacin and equals to opioid analgesics • moderate anti-inflammatory, antipyretic and anti-aggregate effects • high effectiveness in case of pain in postoperative period, in oncology, during child delivery, traumas, colic • i/m, i/v, orally NOT indicated for chronic pain syndrome Ketoprophen (ketonal)

• strong analgesic, anti-inflammatory and antipyretic agent • administered in case of arthroses and arthritis, ancilizing spondilitis, pain of different genesis (after surgeries, in case of traumas, painful menstruations etc.) • administered orally, intramuscularly, in forms of suppositories and ointments TRAMADOL Analgesic activity is similar to the activity of morphine Abuse potential is low Less respiratory depression Hemodynamic effects are minimal In case of intravenous administration effect develops after 5-10 min, if administered orally – after 30-40 min, action lasts for 3-5 hours.

Tramadol possesses agonist actions at the μ-opioid receptor and affects reuptake at the noradrenergic and systems ADMINISTRATION OF TRAMADOL

surgery, traumatology, gynecology, neurology, urology, oncology

For all kinds of acute and chronic pain of moderate and considerable intensity, including neuralgias, postoperative, traumatic pain diagnostic and therapeutic interventions oncologic pathology Thank you!

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