DUROGESIC

SCHEDULING STATUS Schedule 6. PROPRIETARY NAME (and dosage form)

DUROGESIC DUROGESIC25 g/h transdermal therapeutic system DUROGESIC50 g/h transdermal therapeutic system DUROGESIC75 g/h transdermal therapeutic system DUROGESIC100 g/h transdermal therapeutic system
COMPOSITION Each 10 cm transdermal therapeutic system contains 2,5 mg fentanyl, delivering 25 micrograms fentanyl/h. Each 20 cm transdermal therapeutic system contains 5 mg fentanyl, delivering 50 micrograms fentanyl/h. Each 30 cm transdermal therapeutic system contains 7,5 mg fentanyl, delivering 75 micrograms fentanyl/h. Each 40 cm transdermal therapeutic system contains 10 mg fentanyl, delivering 100 micrograms fentanyl/h. PHARMACOLOGICAL CLASSIFICATION A.2.9 Central Nervous System depressants.Other. PHARMACOLOGICAL ACTION Pharmacodynamics Fentanyl is an opioid analgesic, interacting predominantly with the -opioid receptor. Its primary actions of therapeutic value are analgesia and sedation. Minimum effective analgesic serum concentrations of fentanyl in opioid naive patients range from 0,3 - 1,2 ng/mL; side-effects increase in frequency at serum levels above 2 ng/mL. Both the minimum concentration and the concentration at which opioid-related toxicity occurs, rise with increasing patient exposure to the drug. The rate of development of tolerance varies widely among individuals. Pharmacokinetics While there is variation in the dose delivered among patients, the normal flux of the individual system is sufficiently accurate to allow individual titration of dosage for a given patient. DUROGESIC provides nearly constant systemic delivery of fentanyl during the 72 hours application period. Fentanyl is released at a relatively constant rate, determined by the co-polymer release membrane and the diffusion of fentanyl through the skin. After initial DUROGESIC application, serum fentanyl concentrations increase gradually, generally levelling off between 12 and 24 hours and remaining relatively constant for the remainder of the 72 hours application period. Serum fentanyl concentrations attained are proportional to the DUROGESIC patch size. After repeated 72 hour applications, patients reach a steady state serum concentration that is maintained during subsequent applications of the patch of the same size. After DUROGESIC removal, serum fentanyl concentrations decline gradually, falling about 50% in approximately 17 (range: 13-22) hours. Continued absorption of fentanyl from the skin accounts for a slower disappearance of the drug from the serum than is seen after an intravenous infusion. Elderly, cachectic or debilitated patients may have reduced clearance of fentanyl and therefore the agent may have a greatly prolonged terminal half-life in such patients. Fentanyl is metabolised primarily in the liver. Approximately 75% of fentanyl is excreted in urine mostly as metabolites with less than 10% representing unchanged drug. Approximately 9% of the dose is recovered in the faeces, primarily as metabolites. Mean value for unbound fraction of fentanyl in plasma is estimated to be between 13 and 21%. INDICATIONS DUROGESIC is indicated in the management of chronic intractable pain that requires opioid analgesia which cannot be managed by lesser means such as paracetamol-opioid combinations, non-steroidal analgesics or as required

dosing with short acting opioids.. CONTRA-INDICATIONS DUROGESIC is contra-indicated in pregnancy, lactation and children and patients with a known hypersensitivity to fentanyl or to the adhesives present in the transdermal therapeutic system. WARNINGS DUROGESIC SHOULD NOT BE USED IN THE MANAGEMENT OF ACUTE OR POSTOPERATIVE PAIN SINCE SERIOUS OR LIFE THREATENING HYPOVENTILATION COULD RESULT AND THERE IS NO OPPORTUNITY FOR DOSE TITRATION DURING SHORT TERM USE. PATIENTS WHO HAVE EXPERIENCED OPIOID TOXICITY SHOULD BE MONITORED FOR AT LEAST 12 TO 24 HOURS AFTER DUROGESIC REMOVAL SINCE SERUM FENTANYL CONCENTRATIONS DECLINE GRADUALLY AND ARE REDUCED BY 50%, 17 (RANGE: 13-22) HOURS LATER. DUROGESIC SHOULD BE PRESCRIBED ONLY BY PERSONS KNOWLEDGEABLE IN THE CONTINUOUS ADMINISTRATION OF POTENT OPIOIDS; IN THE MANAGEMENT OF PATIENTS RECEIVING POTENT OPIOIDS FOR TREATMENT OF PAIN AND IN THE DETECTION AND MANAGEMENT OF HYPOVENTILATION INCLUDING THE USE OF OPIOID ANTAGONISTS. DOSAGE AND DIRECTIONS FOR USE DUROGESIC doses should be individualised based upon the physical and opioid tolerance status of the patients and should be assessed at regular intervals after application. DUROGESIC should be applied to non-irritated and non-irradiated skin on a flat surface of the torso or upper arms. Hair at the application site (a non-hairy area is preferable) should be clipped (not shaved) prior to application. If the site of DUROGESIC application must be cleansed prior to application of the system, this should be done with clear water. Soap, oils lotions or any other agent that might irritate the skin or alter its characteristics should not be used. The skin should be completely dry before the system is applied. DUROGESIC should be applied immediately upon removal from the sealed package. The transdermal therapeutic system should be pressed firmly in place with the palm of the hand for 30 seconds, making sure the contact is complete, especially around the edges. DUROGESIC may be worn continuously for 72 hours. A new system should be applied on a different skin site after removal of the previous transdermal system. Several days should elapse before a new patch is applied to the same area of the skin. Initial dose selection There has been no systematic evaluation of DUROGESIC as an initial opioid analgesic in the management of chronic pain, since most patients in the clinical trials were converted to DUROGESIC from other narcotics. Therefore, in opioid-nave patients, the lowest DUROGESIC dose, 25 micrograms/h, should be used as the initial dose. In opioid-tolerant patients, to convert from oral to parental opioids to DUROGESIC, the following procedure should be followed: 1 Calculate the previous 24 hour analgesic requirements. 2 Convert this amount to the equianalgesic oral morphine dose using Table 1. All intramuscular and oral doses in this chart are considered equivalent to 10 mg of intramuscular morphine in analgesic effect. 3 Table 2 displays the range of 24 hour oral morphine doses that are recommended for conversion to each DUROGESIC dose. Use this table to derive from the calculated 24 hour morphine dose the corresponding DUROGESIC dose. TABLE 1: Equianalgesic potency conversion DRUG NAME EQUIANALGESIC DOSE (mg) Intramuscular* Morphine Methadone Pethidine Codeine Buprenorphine 10 10 75 130 0,4 Orally 60 (30)** 20 200 0,8 (sublingual)

* Based on single-dose studies in which an intramuscular dose of each drug listed was compared with morphine to establish the relative potency. Oral doses are those recommended when changing from parental to an oral route. ** The oral/intramuscular potency ratio of 1: 3 for morphine is based on clinical experience in patients with chronic pain. TABLE 2: Recommended DUROGESIC dose based upon daily oral morphine dose* Oral 24 hour morphine (mg/day) DUROGESIC dose (micrograms/h) < 135 135-224 225-314 315-404 405-494 495-584 585-674 675-764 765-854 855-944 945-1034 1035-1124 25 50 75 100 125 150 175 200 225 250 275 300

* In clinical trials these ranges of daily oral morphine doses were used as a basis for conversion to DUROGESIC. Both in opioid-naive and opioid-tolerant patients, the initial evaluation of the maximum analgesic effect of DUROGESIC, cannot be made before the system is worn for 24 hours. This delay is due to the gradual increase in serum fentanyl concentration in the 24 hours following initial system application. Previous analgesic therapy should be gradually phased out after the initial dose application until analgesic efficacy with DUROGESIC is attained. Dose titration and maintenance therapy The conversion ratio from oral morphine to DUROGESIC is conservative and 50% of patients are likely to require a dose increase after the initial application. The DUROGESIC patch should be replaced every 72 hours. The dose should be titrated individually until analgesic efficacy is attained. If analgesia is insufficient after the initial application, the dose may be increased after 3 days, based on the daily dose of supplementary analgesics required by the patient in the second or third day of initial application. Thereafter, dose adjustment can take place every 3 days. Physicians are advised that it may take up to 6 days after increasing the dose of DUROGESIC for the patient to reach equilibrium on the new dose. Therefore patients should wear a higher dose through two applications before any further increase in dosage is made, on the basis of the average daily use of a supplemental analgesic. Dosage titration should normally be performed in 25 micrograms/h increments, although the supplementary analgesic requirements (oral morphine 90 mg/day ~ 25 micrograms/h) and pain status of the patient should be taken into account. More than one DUROGESIC system may be used for doses greater than 100 micrograms/h. Patients may require periodic supplementary doses of a short acting analgesic for "breakthrough" pain. Some patients may require additional or alternative methods of opioid administration when the DUROGESIC dose exceed 300 micrograms/h. Discontinuation of DUROGESIC If discontinuation of DUROGESIC is necessary, replacement with other opioids should be gradual, starting at low dose and increasing slowly. This is because fentanyl levels fall gradually after DUROGESIC is removed. It takes 17 hours or more for the fentanyl serum concentrations to decrease 50%. In general, the discontinuation of opioids analgesia should be gradual in order to prevent withdrawal symptoms. Disposal of the patch Used systems should be folded so that the adhesive side of the system adheres to itself, and flushed down the toilet immediately upon removal. Patients should be advised to safely dispose of any system remaining from a prescription

as soon as they are no longer needed. Unused systems should be removed from their pouch and flushed down the toilet. SIDE-EFFECTS AND SPECIAL PRECAUTIONS The most serious side-effect, which can occur throughout the therapeutic range of fentanyl serum concentration is hypoventilation. Other opioid related side-effects reported include: nausea, vomiting, dry mouth, constipation, hypotension and hypertension, bradycardia, somnolence, confusion, hallucinations, euphoria, pruritus, sweating and urinary retention. Skin reactions such as rash, erythema, oedema, papules and itching have occasionally been reported. These reactions resolve after removal of the patch. The following adverse reaction were reported: abdominal pain, abdominal distention, headache, arrhythmia, chest pain, anorexia, diarrhoea, dyspepsia, flatulence, aphasia, asthenia, dizziness, nervousness, anxiety, depression, tremor, abnormal co-ordination, abnormal thinking, abnormal gait, abnormal dreams, agitation, paraesthesia, amnesia, syncope, paranoid reaction, dyspnoea, apnoea, haemoptysis, pharyngitis, hiccups, sweating, hypertonia, vertigo, stupor, hypotonia, depersonalisation, hostility, stertorous breathing, asthma, respiratory disorder, exfoliative dermatitis, pustules, amblyopia, bladder pain, oliguria, urinary frequency. Opioid withdrawal symptoms (such as nausea, vomiting, diarrhoea, anxiety and shivering) are possible in some patients after conversion from their previous opioid analgesic to DUROGESIC. Precautions DUROGESIC should be kept out of reach of children before and after use. DUROGESIC patches should not be divided, cut or damaged in any other way since this leads to uncontrolled release of fentanyl. Some patients may experience significant respiratory depression with DUROGESIC; patients must be observed for these effects. Respiratory depression may persist beyond the removal of the DUROGESIC system. The incidence of respiratory depression increases as the DUROGESIC dose is increased. Central nervous system active agents may increase the respiratory depression. DUROGESIC may have more severe adverse effects in patients with chronic obstructive pulmonary disease, or other pulmonary disease. In such patients, opioids may decrease respiratory drive and increase airway resistance. Tolerance and physical and psychological dependence may develop upon repeated administration of opioids. DUROGESIC should not be used in patients who may be particularly susceptible to the intracranial effects of CO2 retention such as those with evidence of increased intracranial pressure, impaired consciousness, or coma. DUROGESIC should be used with caution in patients with brain tumours. Opioids may obscure the clinical course of patients with head injury. DUROGESIC may produce bradycardia and should therefore be administered with caution to patients with bradyarrhythmias. Presently insufficient information exists to make recommendations regarding the use of DUROGESIC in patients with impaired renal or hepatic functions. If the drug is used in these patients, it should be used with caution because of the hepatic metabolism and limited renal excretion of fentanyl. A pharmacokinetic model suggests that serum fentanyl concentrations may increase by about one third if the skin temperature increases to 40C. Therefore, patients with fever should be monitored for opioid side-effects and the DUROGESIC dose should be adjusted if necessary. All patients should be advised to avoid exposing the DUROGESIC application site to direct external heat sources such as heating pads, electric blankets, heated water beds, heat lamps, intensive sunbathing, hot water bottles, saunas and hot whirlpool spa baths. Data from intravenous studies with fentanyl suggest that elderly patients may have reduced clearance, a prolonged half-life and they may be more sensitive to the drug than younger patients. In studies of DUROGESIC, elderly patients had fentanyl pharmacokinetics which did not differ significantly from young patients although serum concentrations tended to be higher. Elderly patients should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary. The safe use of fentanyl has not been established with respect to possible adverse effects upon foetal development. Therefore, DUROGESIC should not be used in women of childbearing potential unless, in the judgement of the physician, the potential benefits outweighs the possible hazards. Fentanyl is excreted in human milk, therefore DUROGESIC is not recommended for use in nursing women. Interactions The concomitant use of other central nervous system depressants, including other opioids, sedatives, hypnotics, general anaesthetics, phenothiazines, tranquillizers, skeletal muscle relaxants, sedating antihistamines and alcoholic

beverages may produce significant additive depressant effects; hypoventilation, hypotension and profound sedation or coma may occur. Therefore, the use of any of these drugs concomitantly with DUROGESIC requires special patient care and observation. The initial dose of other central nervous system depressants should be reduced by 50%. Fentanyl, a high clearance drug, is rapidly and extensively metabolised mainly by CYP3A4. Itraconazole (a potent CYP3A4 inhibitor) at 200 mg/day given orally for 4 days had no significant effect on the pharmacokinetics of IV fentanyl. Oral ritonavir (one of the most potent CYP3A4 inhibitors) reduced the clearance of IV fentanyl by twothirds. Although clinical data are lacking, in-vitro data suggest that other potent cytochrome P450 3A4 enzyme inhibitors (e.g. fluconazole, ketoconazole, erythromycin, diltiazem and cimetidine) may inhibit the metabolism of fentanyl. The concomitant use of potent CYP3A4 inhibitors such as ritonavir with transdermal fentanyl may result in an increase in fentanyl plasma concentrations, which could increase or prolong both the therapeutic and adverse effects, and may cause serious respiratory depression. In this situation, special patient care and observation are appropriate. The concomitant use of ritonavir and transdermal fentanyl is not recommended, unless the patient is closely monitored. DUROGESIC should be used with caution in patients who have a history of drug or alcohol abuse, especially if they are outside a medically controlled environment. DUROGESIC may impair the mental and/or physical ability required for the performance of potentially hazardous tasks such as driving a car or operating machinery. KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT Symptoms The manifestations of fentanyl overdosage are an extension of its pharmacological action, the most serious effect being respiratory depression. Treatment For the management of respiratory depression, immediate countermeasures include removing the DUROGESIC patch and physically or verbally stimulating the patients. These actions can be followed by administration of the specific narcotic antagonist, naloxone. Respiratory depression following an overdose may outlast the duration of action of the opioid antagonist. The interval between intravenous antagonist doses should be carefully chosen because of the possibility of re-narcotization after system removal; repeated administration of naloxone may be necessary. Reversal of the narcotic effect may result in acute onset of pain and release of catecholamines. If the clinical situation warrants, a patent airway should be established and maintained, possibly with an oropharyngeal airway or endotracheal tube and oxygen should be administered and respiration assisted or controlled, as appropriate. Adequate body temperature and fluid intake should be maintained. If severe or persistent hypotension occurs, the possibility of hypovolemia should be considered and the condition should be managed with appropriate parenteral fluid therapy. IDENTIFICATION DUROGESIC patches are rectangular with round corners, translucent units comprising a protective liner and four functional layers. DUROGESIC patches are available in 4 strengths: DUROGESIC 100 micrograms/h: grey coloured printing DUROGESIC 75 micrograms/h: blue coloured printing DUROGESIC 50 micrograms/h: green coloured printing DUROGESIC 25 micrograms/h: pink coloured printing PRESENTATION DUROGESIC is packed in cartons containing 5 individually packaged systems. STORAGE DIRECTIONS Store below 25C. KEEP OUT OF REACH OF CHILDREN BEFORE AND AFTER USE. REGISTRATION NUMBERS 25 micrograms/h - 28/2.9/0288 50 micrograms/h - 28/2.9/0289 75 micrograms/h - 28/2.9/0290 100 micrograms/h - 28/2.9/0291

NAME AND BUSINESS ADDRESS OF THE APPLICANT JANSSEN - CILAG logo JANSSEN PHARMACEUTICA (PTY) LTD (Reg. No. 1980/011122/07) 15th Road HALFWAY HOUSE, 1685 www.janssencilag.co.za DATE OF PUBLICATION OF THIS PACKAGE INSERT 19 May 1999 Code No: 024398 2003H Britepak Updated on this site: May 2004 Source: Pharmaceutical Industry

Opioids
Compote/Kompot/Polish heroin Diascordium B & Crude opiate O Supprettes Dover's powder Kendal Black Drop extracts/ Laudanum Mithridate Opium Paregoric Poppy whole opium straw concentrate Poppy tea Smoking opium products Theriac Opium Alkaloids see also: Components of Opium Alkaloid Salts Mixtures Codeine Morphine Oripavine Pseudomorphine Thebaine Pantopon Papaveretum (Omnopon) Tetrapon 2-(p-Nitrophenyl)-4isopropylmorphine 14Hydroxymorphine 14 Hydroxymorphine 2,4Dinitrophenylmorphine 6Methyldihydromorphine 6Methylenedihydrodesoxymorphine 6-Acetyldihydromorphine/6Monoacetyldihydromorphine Acetyldihydromorphine Azidomorphine Chlornaltrexamine Chloroxymorphamine Dihydrodesoxymorphine

Natural Opiates Opium and Poppy straw derivatives

Semisynthetic Morphine s Family

(Desomorphine) Dihydromorphine Ethyldihydromorphine Hydromorphinol Methyldesorphine N-Phenethylnormorphine Pseudomorphine RAM-378 6-acetyl-1-iodocodeine 6nicotinoyldihydromorphine Acetylpropionylmorphine Acetylbutyrylmorphine Diacetyldihydromorphine (Dihydroheroin, Acetylmorphinol) Diacetyldibenzoylmorphine 3,6 Diesters of Dibutyrylcodeine Morphine Dibutyrylmorphine Dibenzoylmorphine Diformylmorphine Dipropanoylmorphine Heroin (Diacetylmorphine) Nicomorphine Tetrabenzoylmorphine Tetrabutyrylmorphine 6-Monoacetylcodeine Benzylmorphine Codeine methylbromide Desocodeine Dimethylmorphine (Methocodeine) Dihydroethylmorphine Methyldihydromorphine (Dihydroheterocodeine) Ethylmorphine (Dionine) Heterocodeine Isocodeine Isopropylmorphine Morpholinylethylmorphine (Pholcodine) Myrophine Nalodeine Transisocodeine

CodeineDionine Family

1-Bromohydrocodone 1Bromooxycodone 1Chlorohydrocodone 1Chlorooxycodone 1Iodohydrocodone 1-Iodooxycodone Morphinones 14-Cinnamoyloxycodeinone 14& Morphols Ethoxymetopon 14Methoxymetopon 14 Hydroxymorphone 14Hydroxymorphone 14-OMethyloxymorphone 14Phenylpropoxymetopon 7-

Spiroindanyloxymorphone 8,14Dihydroxydihydromorphinone Acetylcodone Acetylmorphone hydrocodol Bromoisopropropyldihydromorphinon e Codeinone Codorphone Codol Codoxime Thebacon (Acetyldihydrocodeinone / Dihydrocodeinone enol acetate) Ethyldihydromorphinone Hydrocodol Hydrocodone Hydromorphinone Hydromorphol Hydromorphone Hydroxycodeine Isopropropyldihydrocodeinone Isopropropyldihydromorphinone Methyldihydromorphinone Metopon Morphenol Morphinol Morphinone Morphol N-Phenethyl14-ethoxymetopon Oxycodone Oxymorphol Oxymorphinol Oxymorphone Pentamorphone Semorphone -chlorocodide (Alphachlorocodide/Chlorocodide) -chloromorphide 3Bromomorphide Bromocodide Bromomorphide (8-Bromomorphide) Chlorocodide Chloromorphide Codide Fluorocodide (8Fluorocodide) Fluormorphide Iodocodide Iodomorphide (8Iodomorphide) Morphide

Morphides

14-hydroxydihydrocodeine Acetyldihydrocodeine Dihydrocodein Dihydrocodeine Dihydrodesoxycodeine/Desocodeine e Series Dihydroisocodeine Nicocodeine Nicodicodeine Nitrogen Morphine Derivatives Hydrazones 1-Nitrocodeine 2-Nitrocodeine 1Nitromorphine 2-Nitromorphine Codeine-N-Oxide Heroin-N-Oxide Hydromorphone-N-Oxide MorphineN-Oxide Acetylmorphazone Hydromorphazone Morphazone

Oxymorphazone 1-Bromocodeine 2-Bromocodeine 1-Bromodiacetylmorphine 2Bromodiacetylmorphine 1Bromodihydrocodeine 2Bromodihydrocodeine 1Bromodihydromorphine 2Bromodihydromorphine 1Bromomorphine 2-Bromomorphine 1-Chlorocodeine 2-Chlorocodeine 1-Chlorodiacetylmorphine 2Chlorodiacetylmorphine 1Chlorodihydrocodeine 2Chlorodihydrocodeine 1Chlorodihydromorphine 2Chlorodihydromorphine 1Chloromorphine 2-Chloromorphine 1-Fluorocodeine 2-Fluorocodeine 1-Fluorodiacetylmorphine 2Fluorodiacetylmorphine 1Fluorodihydrocodeine 2Fluorodihydrocodeine 1Fluorodihydromorphine 2Fluorodihydromorphine 1Fluoromorphine 2-Fluoromorphine 3-Fluoromorphine 1-Iodocodeine 2Iodocodeine 1Iododiacetylmorphine 2Iododiacetylmorphine 1Iododihydrocodeine 2Iododihydrocodeine 1Iododihydromorphine 2Iododihydromorphine 1Iodomorphine 2-Iodomorphine Chlorethylmorphine Pholcodine

Halogenated Morphine Derivatives

Others

Codeine-N-Oxide (Genocodeine) Dihydromorphine6-glucuronide Hydromorphone-N-Oxide HeroinActive Opiate 7,8-Oxide Morphine-6-glucuronide 6Metabolites Acetylmorphine Morphine-N-Oxide (Genomorphine) Naltrexol Norcodeine Normorphine Morphinans 4-chlorophenylpyridomorphinan Cyclorphan Morphinan Dextrallorphan Dimemorfan Levargorphan Series Levorphanol Levorphan Levophenacylmorphan

Levomethorphan Norlevorphanol NMethylmorphinan Oxilorphan Phenomorphan Methorphan / Racemethorphan Morphanol / Racemorphanol Ro4-1539 Stephodeline Xorphanol 1-Nitroaknadinine 14-episinomenine 5,6Dihydronorsalutaridine 6-Ketonalbuphine Aknadinine Butorphanol Cephakicine Cephasamine Cyprodime Drotebanol Fenfangjine G Nalbuphine Sinococuline Sinomenine (Cocculine) Tannagine

Others

Benzomorphans

5,9-DEHB 8-Carboxamidocyclazocine Alazocine Anazocine Bremazocine Cogazocine Dezocine Eptazocine Etazocine Ethylketocyclazocine Fluorophen Ketazocine Metazocine Pentazocine Phenazocine Quadazocine Thiazocine Tonazocine Volazocine Zenazocine 4-Fluoromeperidine Allylnorpethidine Anileridine Benzethidine Carperidine Difenoxin Diphenoxylate Etoxeridine (Carbetidine) Furethidine Hydroxypethidine (Bemidone) Hydroxymethoxypethidine Morpheridine Pethidines Oxpheneridine (Carbamethidine) Meperidine-N(Meperidines) Oxide Pethidine (Meperidine) Pethidine Intermediate A Pethidine Intermediate B (Norpethidine) Pethidine Intermediate C (Pethidinic Acid) Pheneridine Phenoperidine Piminodine Properidine (Ipropethidine) Sameridine Prodines Allylprodine Isopromedol Meprodine ( meprodine / -meprodine) MPPP (Desmethylprodine) PEPAP Prodine ( -prodine / -prodine) Prosidol Trimeperidine (Promedol)

4-Phenylpiperidines

Acetoxyketobemidone Droxypropine Ketobemidones Ketobemidone Methylketobemidone Propylketobemidone Others Alvimopan Loperamide Picenadol Dextromethadone Dextroisomethadone Dipipanone Hexalgon (Norpipanone) Isomethadone Levoisomethadone Levomethadone Methadone Methadone intermediate Normethadone Norpipanone Phenadoxone (Heptazone) Pipidone Dimepheptanol (Racemethadol) Levacetylmethadol Noracetylmethadol

Open Chain Opioids

Amidones

Methadols

Moramides

Dextromoramide Levomoramide Moramide intermediate Racemoramide

Diallylthiambutene Diethylthiambutene Dimethylthiambutene Ethylmethylthiambutene Methylisopropylthiambutene Thiambutenes Methylpropylthiambutene Morpholinylthiambutene Piperidylthiambutene Pyrrolidinylthiambutene Thiambutene Tipepidine Dextropropoxyphene (Propoxyphene) Dimenoxadol Phenalkoxams Dioxaphetyl Butyrate Levopropoxyphene Norpropoxyphene Ampromides Diampromide Phenampromide Propiram Others IC-26 Isoaminile Lefetamine R-4066 3-Allylfentanyl 3-Methylfentanyl 3-Methylthiofentanyl 4Phenylfentanyl Alfentanil -methylacetylfentanyl methylfentanyl -methylthiofentanyl Benzylfentanyl hydroxyfentanyl -hydroxythiofentanyl -methylfentanyl Brifentanil Carfentanil Fentanyl Lofentanil Mirfentanil Ocfentanil Ohmefentanyl Parafluorofentanyl Phenaridine Remifentanil Sufentanil Thenylfentanyl Thiofentanyl Trefentanil 6,14-Endoethenotetrahydrooripavine 7-PET Acetorphine Alletorphine BU-48 Buprenorphine Butorphine Cyprenorphine Dihydroetorphine Etorphine 18,19Dehydrobuprenorphine (HS-599) N-cyclopropylmethylnoretorphine Nepenthone Norbuprenorphine Nphenethyletorphine Thevinone Thienorphine Ethoheptazine Meptazinol Metheptazine Metethoheptazine Proheptazine Bezitramide Piritramide Clonitazene Etonitazene Nitazene 18-MC 7-Acetoxymitragynine 7-Hydroxymitragynine Akuammidine Akuammine Eseroline Hodgkinsine Mitragynine Pericine -Akuammigine

Anilidopiperidines

Oripavine derivatives

Phenazepanes Pirinitramides Benzimidazoles Indoles

Diphenylmethylpiperazin BW373U86 DPI-221 DPI-287 DPI-3290 SNC-80 es Opioid peptides see also: Opioid Neuropeptides Others Adrenorphin Amidorphin Casomorphin DADLE DALDA DAMGO Dermenkephalin Dermorphin Deltorphin DPDPE Dynorphin Endomorphin Endorphins Enkephalin Gliadorphin Morphiceptin Nociceptin Octreotide Opiorphin Rubiscolin TRIMU 5 3-(3-Methoxyphenyl)-3-ethoxycarbonyltropane AD-1211 AH-

7921 Azaprocin BDPC Bisnortilidine BRL-52537 Bromadoline C-8813 Ciramadol Doxpicomine Enadoline Faxeladol GR-89696 Herkinorin ICI-199,441 ICI-204,448 J113,397 JTC-801 Ketamine LPK-26 Methopholine MT-45 N-Desmethylclozapine NNC 63-0532 Nortilidine ODesmethyltramadol Phenadone Phencyclidine Prodilidine Profadol Ro64-6198 Salvinorin A SB-612,111 SC-17599 RWJ-394,674 TAN-67 Tapentadol Tecodine Tifluadom Tilidine Tramadol Trimebutine U-50,488 U-69,593 Viminol W-18 5'-Guanidinonaltrindole -Funaltrexamine 6 -Naltrexol Alvimopan Binaltorphimine Chlornaltrexamine Clocinnamox Cyclazocine Cyprodime Diprenorphine (M5050) Fedotozine JDTic Levallorphan Methocinnamox Methylnaltrexone Nalfurafine Nalmefene Nalmexone Naloxazone Naloxonazine Naloxone Naloxone benzoylhydrazone Nalorphine Naltrexone Naltriben Naltrindole Norbinaltorphimine Oxilorphan S-allyl-3hydroxy-17-thioniamorphinan (SAHTM) [hide]v d eAnalgesics (N02A, N02B) Opium & alkaloids thereof Semisynthetic opium derivatives Codeine# Morphine# Opium Laudanum Paregoric Acetyldihydrocodeine Benzylmorphine Buprenorphine Desomorphine Dihydrocodeine Dihydromorphine Ethylmorphine Diamorphine Hydrocodone Hydromorphinol Hydromorphone Nicocodeine Nicodicodeine Nicomorphine Oxycodone Oxymorphone Alphaprodine Anileridine Butorphanol Dextromoramide Dextropropoxyphene Dezocine Fentanyl Ketobemidone Levorphanol Methadone Meptazinol Nalbuphine Pentazocine Propoxyphene Propiram Pethidine Phenazocine Piminodine Piritramide Tapentadol Tilidine Tramadol

Opioid Antagonists & Inverse-Agonists

Opioids See also:Opioids template

Synthetic opioids

Pyrazolones Cannabinoids Anilides Non-steroidal anti-inflammatories See also:NSAIDs template

Ampyrone/Aminophenazone Metamizole Phenazone Propyphenazone Ajulemic acid AM404 Cannabidiol Cannabis Nabilone Nabiximols Tetrahydrocannabinol Paracetamol (acetaminophen)# Phenacetin Propacetamol Propionic acid class Fenoprofen Flurbiprofen Ibuprofen# Ketoprofen Naproxen Oxaprozin

Oxicam class Meloxicam Piroxicam

Acetic acid class COX-2 inhibitors Anthranilic acid (fenamate) class Salicylates

Diclofenac Indometacin Ketorolac Nabumetone Sulindac Tolmetin Celecoxib Rofecoxib Valdecoxib Parecoxib Lumiracoxib Meclofenamate Mefenamic acid Aspirin (Acetylsalicylic acid)# Benorylate Diflunisal Ethenzamide Magnesium salicylate Salicin Salicylamide Salsalate Trisalate Wintergreen (Methyl salicylate)

Amitryptiline Befiradol Bicifadine Carisoprodol Camphor Atypical, adjuvant and Cimetidine Clonidine Chlorzoxazone Cyclobenzaprine potentiators, Duloxetine Esreboxetine Flupirtine Gabapentin Glafenine Metabolic agents and Hydroxyzine Ketamine Menthol Mephenoxalone Methocarbamol miscellaneous Nefopam Orphenadrine Pregabalin Proglumide Scopolamine Tebanicline Trazodone XP-13512 (Gabapentin enacarbil) Ziconotide
#

WHO-EM. Withdrawn from market. Clinical trials: Phase III. Never to phase III

M: anat(n/s/m/p/4/e/b/d/c/a/f/l/g)/phys/ noco(m/d/e/h/v/s)/cong/tu proc, CN devp mr, sysi/epon, injr drug(N1A/2AB/C/3/4/7A/B/ S C/D) [hide]v d eSerotonergics [hide] 5-HT1 receptorligands Agonists: Azapirones: Alnespirone Binospirone Buspirone Enilospirone Eptapirone Gepirone Ipsapirone Perospirone Revospirone Tandospirone Tiospirone Umespirone Zalospirone; Antidepressants: Etoperidone Nefazodone Trazodone; Antipsychotics: Aripiprazole Asenapine Clozapine Quetiapine Ziprasidone; Ergolines: Dihydroergotamine Ergotamine Lisuride Methysergide LSD; Tryptamines: 5-CT 5-MeO-DMT 5-MT Bufotenin DMT Indorenate Psilocin Psilocybin; Others: 8-OH-DPAT Adatanserin Befiradol BMY-14802 Cannabidiol Dimemebfe Ebalzotan Eltoprazine F-11,461 F-12,826 F-13,714 F14,679 F-15,063 F-15,599 Flesinoxan Flibanserin Lesopitron Lu AA21004 LY293,284 LY-301,317 MKC-242 NBUMP Osemozotan Oxaflozane Pardoprunox Piclozotan Rauwolscine Repinotan Roxindole RU-24,969 S 14,506 S-14,671 S-15,535 Sarizotan SSR-181,507 Sunepitron U-92,016-A Urapidil Vilazodone Xaliproden Yohimbine Antagonists: Antipsychotics: Iloperidone Risperidone Sertindole; Beta blockers: Alprenolol Cyanopindolol Iodocyanopindolol Oxprenolol Pindobind Pindolol Propranolol Tertatolol; Others: AV965 BMY-7,378 CSP-2503 Dotarizine Flopropione GR-46611 Isamoltane Lecozotan Metitepine/Methiothepin MPPF NAN-190 PRX-00023 Robalzotan S-15535 SB-649,915 SDZ 216-525 Spiperone Spiramide Spiroxatrine UH-301 WAY-100,135 WAY-100,635

5HT1A

Xylamidine Agonists: Lysergamides: Dihydroergotamine Ergotamine Methysergide; Piperazines: Eltoprazine TFMPP; Triptans: Avitriptan Eletriptan Sumatriptan Zolmitriptan; Tryptamines: 5-CT 5-MT; Others: CGS-12066A CP-93,129 CP-94,253 CP135,807 RU-24,969 Antagonists: Lysergamides: Metergoline; Others: AR-A000002 Elzasonan GR127,935 Isamoltane Metitepine/Methiothepin SB-216,641 SB-224,289 SB236,057 Yohimbine Agonists: Lysergamides: Dihydroergotamine Methysergide; Triptans: Almotriptan Avitriptan Eletriptan Frovatriptan Naratriptan Rizatriptan Sumatriptan Zolmitriptan; Tryptamines: 5-CT 5-Ethyl-DMT 5-MT 5-(Nonyloxy)tryptamine; Others: CP-135,807 CP-286,601 GR-46611 L-694,247 L-772,405 PNU-109,291 PNU-142,633 Antagonists: Lysergamides: Metergoline; Others: Alniditan BRL-15,572 Elzasonan GR-127,935 Ketanserin LY-310,762 LY-367,642 LY-456,219 LY-456,220 Metitepine/Methiothepin Ritanserin Yohimbine Ziprasidone

5HT1B

5HT1D

Agonists: Lysergamides: Methysergide; Triptans: Eletriptan; Tryptamines: BRL-54443 5Tryptamine HT1E Antagonists: Metitepine/Methiothepin Agonists: Triptans: Eletriptan Naratriptan Sumatriptan; Tryptamines: 5-MT; Others: 5BRL-54443 Lasmiditan LY-334,370 HT1F Antagonists: Metitepine/Methiothepin [hide] 5-HT2 receptor ligands Agonists: Lysergamides: ALD-52 Ergometrine Lisuride LA-SS-Az LSD LSDPip Lysergic acid 2-butyl amide Lysergic acid 3-pentyl amide Methysergide; Phenethylamines: 25I-NBF 25I-NBMD 25I-NBOH 25I-NBOMe 2C-B 2C-BFLY 2CB-Ind 2C-C-NBOMe 2C-E 2C-I 2C-TFM-NBOMe 2C-T-2 2C-T-7 2C-T-21 2CBCB-NBOMe 2CBFly-NBOMe Bromo-DragonFLY DOB DOC DOI DOM MDA MDMA Mescaline TCB-2 TFMFly; Piperazines: BZP Quipazine TFMPP; Tryptamines: 5-CT 5-MeO- -ET 5-MeO- -MT 5-MeO-DET 5-MeO-DiPT 5-MeO-DMT 5-MeO-DPT 5-MT -ET -Methyl-5-HT -MT Bufotenin DET DiPT DMT DPT Psilocin Psilocybin; Others: AL-34662 AL37350A Dimemebfe Medifoxamine Oxaflozane PNU-22394 RH-34 Antagonists: Atypical antipsychotics: Amperozide Aripiprazole Carpipramine Clocapramine Clozapine Gevotroline Iloperidone Melperone Mosapramine Olanzapine Paliperidone Pimozide Quetiapine Risperidone Sertindole Ziprasidone Zotepine; Typical antipsychotics: Loxapine Pipamperone; Antidepressants: Amitriptyline Amoxapine Aptazapine Etoperidone Mianserin Mirtazapine Nefazodone Trazodone; Others: 5-I-R91150 AC-90179 Adatanserin Altanserin AMDA APD-215 Blonanserin Cinanserin CSP-2503 Cyproheptadine Deramciclane Dotarizine Eplivanserin Esmirtazapine Fananserin Flibanserin Ketanserin KML-010 Lubazodone Mepiprazole Metitepine/Methiothepin Nantenine Pimavanserin Pizotifen Pruvanserin Rauwolscine Ritanserin S-14,671 Sarpogrelate Setoperone Spiperone

5HT2A

Spiramide SR-46349B Volinanserin Xylamidine Yohimbine Agonists: Oxazolines: 4-Methylaminorex Aminorex; Phenethylamines: Chlorphentermine Cloforex DOB DOC DOI DOM Fenfluramine MDA MDMA Norfenfluramine; Tryptamines: 5-CT 5-MT -Methyl-5-HT; Others: BW723C86 Cabergoline mCPP Pergolide PNU-22394 Ro60-0175 Antagonists: Agomelatine Asenapine EGIS-7625 Ketanserin Lisuride LY272,015 Metitepine/Methiothepin PRX-08066 Rauwolscine Ritanserin RS127,445 Sarpogrelate SB-200,646 SB-204,741 SB-206,553 SB-215,505 SB221,284 SB-228,357 SDZ SER-082 Tegaserod Yohimbine Agonists: Phenethylamines: 2C-B 2C-E 2C-I 2C-T-2 2C-T-7 2C-T-21 DOB DOC DOI DOM MDA MDMA Mescaline; Piperazines: Aripiprazole mCPP TFMPP; Tryptamines: 5-CT 5-MeO- -ET 5-MeO- -MT 5-MeO-DET 5-MeODiPT 5-MeO-DMT 5-MeO-DPT 5-MT -ET -Methyl-5-HT -MT Bufotenin DET DiPT DMT DPT Psilocin Psilocybin; Others: A-372,159 AL38022A CP-809,101 Dimemebfe Lorcaserin Medifoxamine MK-212 Org 12,962 ORG-37,684 Oxaflozane PNU-22394 Ro60-0175 Ro60-0213 Vabicaserin WAY-629 WAY-161,503 YM-348 Antagonists: Atypical antipsychotics: Clozapine Iloperidone Melperone Olanzapine Paliperidone Pimozide Quetiapine Risperidone Sertindole Ziprasidone Zotepine; Typical antipsychotics: Chlorpromazine Loxapine Pipamperone; Antidepressants: Agomelatine Amitriptyline Amoxapine Aptazapine Etoperidone Fluoxetine Mianserin Mirtazapine Nefazodone Nortriptyline Trazodone; Others: Adatanserin Cinanserin Cyproheptadine Deramciclane Dotarizine Eltoprazine Esmirtazapine FR-260,010 Ketanserin Ketotifen Latrepirdine Lu AA24530 Metitepine/Methiothepin Methysergide Pizotifen Ritanserin RS-102,221 S14,671 SB-200,646 SB-206,553 SB-221,284 SB-228,357 SB-242,084 SB243,213 SDZ SER-082 Xylamidine [hide] 5-HT3, 5-HT4, 5-HT5, 5-HT6, 5-HT7 ligands Agonists: Piperazines: BZP Quipazine; Tryptamines: 2-Methyl-5-HT 5-CT; Others: Chlorophenylbiguanide Butanol Ethanol Halothane Isoflurane RS-56812 SR57,227 SR-57,227-A Toluene Trichloroethane Trichloroethanol Trichloroethylene YM-31636 Antagonists: Antiemetics: AS-8112 Alosetron Azasetron Batanopride Bemesetron Cilansetron Dazopride Dolasetron Granisetron Lerisetron Ondansetron Palonosetron Ramosetron Renzapride Tropisetron Zacopride Zatosetron; Atypical antipsychotics: Clozapine Olanzapine Quetiapine; Tetracyclic antidepressants: Amoxapine Mianserin Mirtazapine; Others: CSP-2503 ICS-205,930 Lu AA21004 Lu AA24530 MDL-72,222 Memantine Nitrous Oxide Ricasetron Sevoflurane Thujone Xenon Agonists: Gastroprokinetic Agents: Cinitapride Cisapride Dazopride Metoclopramide Mosapride Prucalopride Renzapride Tegaserod Zacopride; Others: 5-MT BIMU8 CJ-033,466 PRX-03140 RS-67333 RS-67506 SL65.0155 TD-5108 Antagonists: GR-113,808 GR-125,487 L-Lysine Piboserod RS-39604 RS-67532

5HT2B

5HT2C

5HT3

5HT4

SB-203,186 Agonists: Lysergamides: Ergotamine LSD; Tryptamines: 5-CT; Others: Valerenic Acid 5Antagonists: Asenapine Latrepirdine Metitepine/Methiothepin Ritanserin SBHT5A 699,551 *Note that the 5-HT5B receptor is not functional in humans. Agonists: Lysergamides: Dihydroergotamine Ergotamine Lisuride LSD Mesulergine Metergoline Methysergide; Tryptamines: 2-Methyl-5-HT 5-BT 5-CT 5-MT Bufotenin E-6801 E-6837 EMD-386,088 EMDT LY-586,713 N-Methyl5-HT Tryptamine; Others: WAY-181,187 WAY-208,466 Antagonists: Antidepressants: Amitriptyline Amoxapine Clomipramine Doxepin Mianserin Nortriptyline; Atypical antipsychotics: Aripiprazole Asenapine Clozapine Fluperlapine Iloperidone Olanzapine Tiospirone; Typical antipsychotics: Chlorpromazine Loxapine; Others: BGC20-760 BVT-5182 BVT-74316 EGIS12,233 GW-742,457 Ketanserin Latrepirdine Lu AE58054 Metitepine/Methiothepin MS-245 PRX-07034 Ritanserin Ro04-6790 Ro 630563 SB-258,585 SB-271,046 SB-357,134 SB-399,885 SB-742,457 Agonists: Lysergamides: LSD; Tryptamines: 5-CT 5-MT Bufotenin; Others: 8-OHDPAT AS-19 Bifeprunox LP-12 LP-44 RU-24,969 Sarizotan Antagonists: Lysergamides: 2-Bromo-LSD Bromocriptine Dihydroergotamine Ergotamine Mesulergine Metergoline Methysergide; Antidepressants: Amitriptyline Amoxapine Clomipramine Imipramine Maprotiline Mianserin; Atypical antipsychotics: Amisulpride Aripiprazole Clozapine Olanzapine Risperidone Sertindole Tiospirone Ziprasidone Zotepine; Typical antipsychotics: Chlorpromazine Loxapine; Others: Butaclamol EGIS-12,233 Ketanserin LY215,840 Metitepine/Methiothepin Pimozide Ritanserin SB-258,719 SB-258,741 SB-269,970 SB-656,104 SB-656,104-A SB-691,673 SLV-313 SLV-314 Spiperone SSR-181,507 [hide] Reuptake inhibitors Selective serotonin reuptake inhibitors (SSRIs): Alaproclate Citalopram Dapoxetine Desmethylcitalopram Desmethylsertraline Escitalopram Femoxetine Fluoxetine Fluvoxamine Indalpine Ifoxetine Litoxetine Lu AA21004 Lubazodone Panuramine Paroxetine Pirandamine RTI-353 Seproxetine Sertraline Vilazodone Zimelidine; Serotonin-norepinephrine reuptake inhibitors (SNRIs): Bicifadine Desvenlafaxine Duloxetine Eclanamine Levomilnacipran Milnacipran Sibutramine Venlafaxine; Serotonin-norepinephrine-dopamine reuptake inhibitors (SNDRIs): Brasofensine Diclofensine DOV-102,677 DOV-21,947 SERT DOV-216,303 NS-2359 SEP-225289 SEP-227,162 Tesofensine; Tricyclic antidepressants (TCAs): Amitriptyline Butriptyline Cianopramine Clomipramine Desipramine Dosulepin Doxepin Imipramine Lofepramine Nortriptyline Pipofezine Protriptyline Trimipramine; Tetracyclic antidepressants (TeCAs): Amoxapine; Piperazines: Nefazodone Trazodone; Antihistamines: Brompheniramine Chlorphenamine Diphenhydramine Mepyramine/Pyrilamine Pheniramine Tripelennamine; Opioids: Pethidine Methadone Propoxyphene; Others: Cocaine CP-39,332 Cyclobenzaprine Dextromethorphan Dextrorphan EXP-561

5HT6

5HT7

Fezolamine Mesembrine Nefopam PIM-35 Pridefine Roxindole SB-649,915 Ziprasidone VMAT Ibogaine Reserpine Tetrabenazine [hide] Releasing agents Aminoindanes: 5-IAI AMMI ETAI MDAI MDMAI MMAI TAI; Aminotetralins: 6CAT 8-OH-DPAT MDAT MDMAT; Oxazolines: 4-Methylaminorex Aminorex Clominorex Fluminorex; Phenethylamines (also Amphetamines, Cathinones, Phentermines, etc): 2-Methyl-MDA 4-CAB 4-FA 4-FMA 4-HA 4-MTA 5-APDB 5-Methyl-MDA 6-APDB 6-Methyl-MDA AEMMA Amiflamine BDB BOH Brephedrone Butylone Chlorphentermine Cloforex Amfepramone Metamfepramone DFMDA DMA DMMA EBDB EDMA Ethylone Etolorex Fenfluramine (Dexfenfluramine) Flephedrone IAP IMP Lophophine MBDB MDA MDEA MDHMA MDMA MDMPEA MDOH MDPEA Mephedrone Methedrone Methylone MMA MMDA MMDMA MMMA NAP Norfenfluramine 4-TFMA pBA pCA pIA PMA PMEA PMMA TAP; Piperazines: 2C-B-BZP 2-BZP 3-MeOPP BZP DCPP MBZP mCPP MDBZP MeOPP Mepiprazole pCPP pFPP pTFMPP TFMPP; Tryptamines: 4-Methyl- ET 4Methyl- MT 5-CT 5-MeO- ET 5-MeO- MT 5-MT ET MT DMT Tryptamine (itself); Others: Indeloxazine Tramadol Viqualine [hide] Enzyme inhibitors Anabolism TPH AGN-2979 Fenclonine AAAD Benserazide Carbidopa Genistein Methyldopa

Nonselective: Benmoxin Caroxazone Echinopsidine Furazolidone Hydralazine Indantadol Iproclozide Iproniazid Isocarboxazid Isoniazid Linezolid Mebanazine Metfendrazine Nialamide Octamoxin Paraxazone Phenelzine Pheniprazine Phenoxypropazine Pivalylbenzhydrazine Procarbazine Safrazine Tranylcypromine; MAO-A Catabolism MAO Selective: Amiflamine Bazinaprine Befloxatone Befol Brofaromine Cimoxatone Clorgiline Esuprone Harmala alkaloids (Harmine, Harmaline, Tetrahydroharmine, Harman, Norharman, etc) Methylene Blue Metralindole Minaprine Moclobemide Pirlindole Sercloremine Tetrindole Toloxatone Tyrima [hide] Others Precursors L-Tryptophan
2+

5-HTP

Ferrousiron (Fe ) Magnesium (Mg2+) Tetrahydrobiopterin Vitamin B3 (Niacin, Nicotinamide NADPH) Vitamin B6 (Pyridoxine, Pyridoxamine, Pyridoxal Cofactors Pyridoxal phosphate) Vitamin B9 (Folic Acid Tetrahydrofolic acid) Vitamin C (Ascorbic acid) Zinc (Zn2+) Others Activity enhancers: BPAP PPAP; Reuptake enhancers: Tianeptine Categories: Convulsants | Synthetic opioids | Piperidines | Ethyl esters | Mu-opioid agonists