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Biological: Behavioural genetics · Evolutionary psychology · Neuroanatomy · Neurochemistry · Neuroendocrinology · Neuroscience · Psychoneuroimmunology · Physiological Psychology · Psychopharmacology (Index, Outline)
Tapentadol chemical structure | |
3-[(1R,2R)-3-(dimethylamino)-1-ethyl-2- methylpropyl]phenol hydrochloride IUPAC name | |
CAS number 175591-09-0 |
ATC code |
PubChem 9838022 |
DrugBank [1] |
Chemical formula | {{{chemical_formula}}} |
Molecular weight | 221.339 g/mol |
Bioavailability | 31.9 ± 6.8% (oral)[1] |
Metabolism | Hepatic glucuronidation and sulfate conjugation |
Elimination half-life | 4 hrs |
Excretion | Renal (>95%) and fecal |
Pregnancy category | {{{pregnancy_category}}} |
Legal status | Schedule II |
Routes of administration | Oral, Other ROA Unknown |
Tapentadol (trade names: Nucynta, Palexia, in India available as TAPAL by MSN Labs) [2] is a centrally acting analgesic with a dual mode of action as an agonist of the μ-opioid receptor and as a norepinephrine reuptake inhibitor.[3] It is also an agonist of the σ2 receptor, though the function of this orphan receptor remains controversial.[3]
Similar to levorphanol—another opioid with serotonin–norepinephrine reuptake inhibitor (SNRI) effects—in its dual mechanism of action, tapentadol provides analgesia comparable to other opioid analgesics such as hydrocodone, oxycodone, and pethidine (meperidine) but with a more tolerable side effect profile. While its analgesic actions have been compared to tramadol and oxycodone,[4] its general potency is somewhere between tramadol and morphine in effectiveness.[5]
Tapentadol was originally approved by the U.S. Food and Drug Administration (FDA) in November 2008, for the treatment of moderate to severe acute pain, and in 2011, the extended-release formulation (Nucynta ER) was approved by the US FDA for the treatment of select types of moderate to severe chronic pain. Due to the dual mechanism of action as an opioid agonist and norepinephrine reuptake inhibitor, there is also potential for off-label use in chronic pain and certain mood disorders (similar to off-label use of tramadol). Physicians use SNRIs in chronic pain management to increase the effectiveness of opioids and other analgesics such as NSAIDs against neuropathic pain and from certain specific contributing causes such as fibromyalgia and diabetic neuropathy. One SNRI often used as an adjunct, atypical & potentiator is duloxetine (Cymbalta).
History[]
Tapentadol was developed by Grünenthal in conjunction with Johnson & Johnson Pharmaceutical Research and Development. It is being marketed as immediate release oral tablets of 50 mg, 75 mg, and 100 mg under the brand name Nucynta.
It is the first new drug of the centrally acting analgesic class approved in the United States in more than 25 years.[6] Internationally, tapentadol's status is in various stages of development at this time.
- On 23 January 2008, a New Drug Application (NDA) for tapentadol was submitted to the U.S. FDA.
- On 21 November 2008, Johnson & Johnson announced that it has received approval for immediate-release tapentadol tablets.[7]
- On 17 February 2009 the U.S. Drug Enforcement Administration proposed a rule which would add tapentadol to Schedule II of the Controlled Substances Act of 1970.[8] The original commercial release date for tapentadol was planned for 17 March 2009; however, the placement of the compound in Schedule II interrupted commercial development. It was the manufacturer's intention to have tapentadol approved as a Schedule III compound, based upon limited preclinical animal data that show a reduced liability for abuse and tolerance compared with morphine.
- On 22 June 2009, the Drug Enforcement Administration approved the proposal to make tapentadol schedule II under the Controlled Substance Act.
- On 23 June 2009, after having received approval from the FDA and DEA, tapentadol became available for prescription on the US market. It is available in immediate-release oral doses of 50, 75, and 100 mg.
- On 10 August 2010, the European decentralised procedure regarding tapentadol concluded positively, which will result in the granting of national marketing authorisations in 26 European markets. Tapentadol will then be available as an oral, solid, immediate-release formulation (tablets) for the relief of moderate to severe acute pain in adults, which can be adequately managed only with opioid analgesics, and an oral, solid, prolonged-release formulation (tablets) for the management of severe chronic pain in adults, which can be adequately managed only with opioid analgesics.
- On 28 March 2011 the United Kingdom made tapentadol a Class A controlled drug.[9]
Clinical trials[]
The efficacy of tapentadol compared to a placebo was demonstrated in two phase III (and one phase II) randomized, double-blind, multi-center, placebo-controlled clinical trials submitted to the United States Food and Drug Administration. The phase III trials evaluated tapentadol multiple dosing following orthopedic surgery and in late-stage osteoarthritis (OA). The phase II study evaluated single dosing of tapentadol following a dental procedure. All trials utilized a zero-to-ten-point scale for pain intensity (none to worst) and a zero-to-five-point scale for pain relief (none to complete). Patients were assessed at intervals; the sum of numerical values for these pain scales were the basis of evaluating efficacy. Secondary endpoints of total pain relief from baseline, time to pain relief, time to first rescue medication and the need for rescue medication are clinically relevant endpoints. These published phase II and phase III studies used active control medications, including oxycodone, morphine or NSAIDs.
Tapentadol demonstrated efficacy compared with a placebo in a phase III, three-day, multiple-dosing assessment of post-surgical (bunionectomy) pain. The mean age of this patient population was 60–62 years. Participants had a post-operative baseline pain score of>4 on an 11-point scale, and were randomized to placebo, tapentadol 50 mg, 75 mg, 100 mg or oxycodone IR 15 mg. All study medications (including oxycodone) were compared to placebo and given every four to six hours. The sum of pain intensity difference (SPID) over the first 48 hours of study medication improved with all tapentadol strengths and oxycodone, compared with a placebo (p=<0.001). The percentage of patients requiring rescue medication was less for tapentadol and oxycodone, compared with a placebo (tapentadol 100 mg 10 percent, oxycodone 15 mg 9 percent, placebo 49 percent). The time to the first dose of rescue medication required was reduced with all strengths of tapentadol and oxycodone compared with a placebo (p=<0.001, no data given). Overall, more patients experienced at least a 50-percent improvement in pain from baseline levels with tapentadol and oxycodone compared with placebo (tapentadol 50, 75, 100 mg 58 percent, 56.7 percent, 70.3 percent, oxycodone 72.8 percent, placebo 30 percent, p=<0.001). Absolute risk reduction (ARR) was 40.3 percent for Tapentadol 100 mg and 42.8 percent for oxycodone. The number needed to treat (NNT) for 50-percent pain improvement at 48 hours was 3.6, 3.8 and 2.5 for tapentadol and 2.5 for oxycodone. Tapentadol was non-inferior to oxycodone IR 15 mg. Withdrawal due to adverse events was less with Tapentadol than oxycodone (NNH; Tapentadol 50, 75, 100 mg=39, 23.8, n/a, oxycodone=100).[10]
Tapentadol was effective in a phase III, 10-day, multiple-dosing assessment of patients awaiting knee-replacement surgery from late-stage OA. All patients were at a level of pain indicating opioid analgesics. Tapentadol 50 mg, 75 mg and oxycodone IR 10 mg was compared to a placebo. The SPID at 48 hours and 5 days improved with tapentadol 50 and 75 mg and oxycodone 10 mg compared to placebo (p=<0.001). More patients experienced at least a 50-percent improvement in pain from baseline with tapentadol and oxycodone compared to placebo (tapentadol=27, 26, oxycodone=25 percent, placebo=13 percent, p=<0.01). The number of doses needed (NNT) for 50-percent pain relief was 7.1, 7.7 and 8.3 for tapentadol 50 and 75 mg doses and oxycodone. Tapentadol was non-inferior to oxycodone IR 15 mg. In this 10-day study, tapentadol had a lower incidence of discontinuation due to adverse events than oxycodone (NNH tapentadol 50,75 mg=11.2, 6.9, oxycodone=3.6). The authors also reported a lower incidence of selected gastrointestinal adverse events with tapentadol (p=<0.001).[11]
A phase II, single-dose trial of tapentadol 25 mg-200 mg, ibuprofen 400 mg and morphine IR 60 mg was evaluated for post-surgical dental pain. This patient population was younger than in the previous two studies (18–45 years old, mean age 23). The SPID at four and eight hours improved from baseline compared to placebo with doses of tapentadol that were>75 mg (p=<0.05). The time to noticeable, clinically meaningful pain relief reported by patients was shorter for tapentadol 200 mg and ibuprofen 400 mg compared to morphine 60 mg IR (time to perceptible, meaningful pain relief: tapentadol 200 mg=0.7 hours, 1.5 hours, morphine 60 mg=0.8 hours, 2.6 hours, ibuprofen 400 mg=0.8 hours, 1.5 hours). A minimum dose of 50 mg tapentadol was necessary to achieve statistical significance for a 50-percent reduction in pain from baseline. More patients reported a 50-percent improvement in pain from baseline with each increasing dose of tapentadol. The NNT for tapentadol 50, 75, 100, 200 mg was 13, 5, 2, and 3, compared with an NNT for morphine 60 mg and ibuprofen 400 mg of 3 and 2, respectively. Ibuprofen appeared to work well compared to other medications in this model.[12]
Non-published studies have evaluated tapentadol with oxycodone and placebo in hip-replacement surgery (terminated due to high discontinuation rates) and tapentadol with morphine and placebo in chronic tumor-related pain (terminated due to the recall of a rescue medication, impacting the study's timeline). Results of these studies are not available. Studies recruiting subjects include tapentadol, morphine and placebo in chronic tumor-related pain and tapentadol, oxycodone and placebo in post-operative shoulder-surgery and vertebral compression-fracture pain. There have been no listed clinical trials involving tramadol or NSAIDs.[citation needed]
Indications[]
Tapentadol is indicated for the treatment of moderate to severe pain for both acute (following injury, surgery, etc.) and chronic musculoskeletal pain. It is also specifically indicated for controlling the pain of diabetic neuropathy when around-the-clock opioid medication is required.[13] Although tapentadol is not indicated for the treatment of non-diabetic neuropathic pain, it is often used off-label for this purpose.[14] It also has the potential to treat depression like its close relative, tramadol, but it is not approved for this indication either.[15]
Availability and dosage[]
Tapentadol is available in the United States in both immediate release and extended release formulations as Nucynta and Nucynta ER, respectively, from Janssen Pharmaceuticals. The immediate release formulation is provided in 50 mg (yellow), 75 mg (orange), and 100 mg (red/orange) tablets, to be used once every 4–6 hours as needed to control pain, up to a maximum dose of 600 mg per 24 hour period (700 mg on day one).[16] The extended release formulation is provided in 50 mg (white), 100 mg (very light blue), 150 mg (light blue), 200 mg (blue), and 250 mg (dark blue). The extended release dosage starts at 50 mg twice a day, and is then slowly titrated to an effective and tolerable dose in the range of 100 mg-250 mg twice a day, with a maximum dose of 500 mg (250 mg twice a day) per 24 hour period.[17] The dosage and preparation used should be frequently re-evaluated by the prescribing physician, and the dose should be lowered if possible to the lowest effective dose if pain decreases.[18]
All preparations of Nucynta contain only the (R,R) stereoisomer, which is the weakest isomer in terms of opioid activity.[19] (See "Tramadol" for more information on tapentadol's chemistry)
Cost[]
As it is not currently available in generic form, Nucynta will cost the patient several hundred dollars per monthly supply without insurance ($2.96-$8.98 per pill).[20] To make Nucynta more competitive, Janssen Pharmaceuticals offers a Nucynta savings card to patients with valid health insurance (with the exception of medicare, medicaid, and other federally sponsored insurance plans) which enables them to pay no more than $25 per month for any preparation (up to 14 times per year for ER preparations and up to 3 times per year for IR preparations).[21]
Mechanism of action[]
Although the manufacturer currently lists Nucynta's mechanism of action as unknown, they state that it is most likely (as it is generally accepted to be) a combination of an agonistic effect at the mu-opioid receptor and the inhibition of norepinephrine re-uptake.[22] Tapentadol has also been demonstrated to be sigma-2 receptor agonist.
Adverse effects[]
Nausea, dizziness, constipation, and CNS sedation are common side effects of opioid pain medications. In phase II trials, tapentadol has been shown to provide equianalgesic effect with a lower incidence of side effects compared to oxycodone and morphine. One trial, sponsored by Grünenthal, comparing tapentadol to morphine and ibuprofen for relief of postoperative pain found tapentadol to cause less nausea and dizziness than morphine, with no significant difference in the incidence of vomiting or drowsiness.[23]
Tapentadol may impair physical and cognitive abilities and should not be used when operating heavy machinery, especially during initial treatment and following increases in dosage. Patients should not attempt to operate any vehicle until they know how tapentadol affects them.[24]
The regular use of Nucynta will generally result in dependence and can lead to addiction, producing unpleasant withdrawal symptoms when the dependent person attempts to abruptly discontinue use of the drug. Withdrawal may also be elicited in Nucynta users if they are administered an opioid antagonist such as naloxone, or mixed opioid agonist/antagonists such as buprenorphine.[25]
Clinical studies cite there is less incidence of select adverse gastrointestinal effects with the administration of tapentadol when compared to oxycodone.[26]
A relative high incidence of hallucinations have been reported, especially among patients on anti-depressants, possibly due to its pro-adrenergic properties.[26][27]
Combination with SSRIs/SNRIs, SRAs, serotonin receptor agonists and/or MAOIs may lead to potentially lethal serotonin syndrome.[28] Combination with MAOIs may also result in an adrenergic storm.
Contraindications[]
Tapentadol may increase the risk of seizures, and should be administered with care to epileptic patients and patients who are taking other drugs which lower the seizure threshold.[29]
Since tapentadol may increase intracranial pressure by depressing respiration and increasing CO2 retention, it should not be administered to patients suffering from head injuries, brain tumors, or other conditions which increase intracranial pressure.[29]
Taptentadol is contraindicated in patients with severe bronchial asthma, hypercapnia, and patients who have or are suspected to have paralytic ileus, due to the increased risk of respiratory depression.[29]
Due to reduced clearance, tapentadol should be administered with caution to patients with moderate hepatic impairment (with reduced dosage), and not at all in patients with severe hepatic impairment.[29]
As with other mu-opioid agonists, tapentadol may cause spasms of the Sphincter of Oddi, and is therefore discouraged for use in patients with biliary tract disease such as acute pancreatitis.[29]
No human control studies have been conducted regarding the safety of tapentadol during pregnancy, although animal studies have suggested that it poses a risk of emryofetal toxicity.[30] As such, the U.S. Food and Drug Administration (FDA) has placed it into pregnancy category C. Women should avoid taking tapentadol during pregnancy unless the benefit outweighs the risk to the fetus.[29]
Abuse potential[]
From Janssen Pharmaceuticals, Inc: "NUCYNTA is a mu-opioid agonist and is a Schedule II controlled substance. Such drugs are sought by drug abusers and people with addiction disorders. Diversion of Schedule II products is an act subject to criminal penalty. NUCYNTA can be abused in a manner similar to other mu-opioid agonists, legal or illicit. This should be considered when prescribing or dispensing NUCYNTA in situations where the physician or pharmacist is concerned about an increased risk of misuse and abuse. All patients treated with mu-opioid agonists require careful monitoring for signs of abuse and addiction. NUCYNTA may be abused by crushing, chewing, snorting or injecting the product. These practices pose a significant risk to the abuser that could result in overdose and death."[29] Patients with a history of drug or alcohol abuse are believed to have a higher risk of abusing NUCYNTA, as with other mu-opioid agonists.[25]
Although early pre-clinical animal trials suggested that Nucynta has a reduced abuse liability compared to other opioid analgesics, it has since been determined to be no less abusable than other pure-form opioid preparations. The US DEA has placed tapentadol into Schedule II,[31] the same category as the most powerful and frequently abused narcotics, such as morphine, oxycodone, and fentanyl.[32][33]
Overdose[]
Experience with Tapentadol overdose is very limited. Management of overdose should be focused on treating symptoms of mu-opioid agonism. Primary attention should be given to reestablishment of a patent airway and institution of assisted or controlled ventilation when overdose of Tapentadol is suspected. Supportive measures (including oxygen and vasopressors) should be employed in the management of circulatory shock and pulmonary edema accompanying overdose as indicated. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation.[29]
Due to its actions on norepinephrine, and to a lesser extent serotonin, a Tapentadol overdose may produce symptoms which are not typically present in opioid overdoses (symptoms of serotonin syndrome and adrenergic syndrome). This risk is greater if Tapentadol has been taken with other drugs of similar mechanisms.[29] These additional symptoms should be addressed and treated symptomatically (after treating for mu-opioid agonism) if they are presented and must be taken into consideration prior to the administration of any medication.[34] It may be necessary to treat the patients convulsions first in order to safely achieve intubation.
Tapentadol overdose is more likely to occur when it is combined with alcohol or other drugs. Alcohol administration has been demonstrated to increase the plasma levels of Tapentadol, thereby increasing the effect of the Tapentadol as well as acting synergistically with the depressant effects of alcohol.[29] The concomitant use of Tapentadol and other depressants (including alcohol) significantly increases the risks of somnolence, hypotension, coma, and (potentially fatal) respiratory depression.[29]
See also[]
- Bromadol
- C-8813
- Ciramadol
- Faxeladol
- O-desmethyltramadol
- Profadol
- Tramadol
References[]
- ↑ Terlinden, R.; Ossig, J.; Fliegert, F.; Gohler, K. (2006). "Pharmacokinetics, Excretion and Metabolism of Tapentadol HCl, a Novel Centrally Acting Analgesic in Healthy Subjects" Program and Abstracts of the 25th Annual Scientific Meeting of the American Pain Society; May 3–6, 2006 San Antonio, Texas. Poster 689.
- ↑ Template:Cite patent
- ↑ 3.0 3.1 Tzschentke, T. M.; Christoph, T.; Kögel, B.; Schiene, K.; Hennies, H. H.; Englberger, W.; Haurand, M.; Jahnel, U.; Cremers, T. I.; Friderichs, E.; De Vry, J. (2007). (-)-(1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol Hydrochloride (Tapentadol HCl): A Novel μ-Opioid Receptor Agonist / Norepinephrine Reuptake Inhibitor with Broad-Spectrum Analgesic Properties. Journal of Pharmacology and Experimental Therapeutics 323 (1): 265–76.
- ↑ Data Comparing Nucynta (Tapentadol) Tablets to Oxycodone Immediate Release Tablets Presented at 2010 American Pain Society Annual Meeting. MedNews. Drugs.com.
- ↑ Tzschentke, T. M.; de Vry, J.; Terlinden, R.; Hennies, H.-H.; Lange, C.; Strassburger, W.; Haurand, M.; Kolb, J.; Schneider, J.; Buschmann, H.; Finkam, M.; Jahnel, U.; Friedrichs, E. (2006). Tapentadol Hydrochloride. Drugs of the Future 31 (12).
- ↑ includeonly>Krüger-Hellwig, A.. "Grünenthal GmbH Presents Tapentadol, a Novel Centrally Acting Analgesic, at the 25th Annual Scientific Meeting of The American Pain Society", 6 June 2006. Retrieved on 2007-09-20.
- ↑ FDA Approves Tapentadol Immediate-Release Tablets for Relief of Moderate to Severe Acute Pain November 21, 2008. Retrieved on November 24, 2008.
- ↑ Proposed Rule - Schedules of Controlled Substances: Placement of Tapentadol Into Schedule II (February 17, 2009)
- ↑ Misuse of Drugs Act 1971 (Amendment) Order 2011
- ↑ Daniels, S.; Upmalis, D.; Okamoto, A.; Lange, C.; Haeussler, J. (2009). A Randomized, Double-Blind, Phase III Study Comparing Multiple Doses of Tapentadol IR, Oxycodone IR, and Placebo for Postoperative (bunionectomy) Pain. Current Medical Research and Opinion 25 (3): 765–76.
- ↑ Hartrick, C.; van Hove, I.; Stegmann, J.-U.; Oh, C.; Upmalis, D. (2009). Efficacy and Tolerability of Tapentadol Immediate Release and Oxycodone HCl Immediate Release in Patients Awaiting Primary Joint Replacement Surgery for End-Stage Joint Disease: A 10-Day, Phase III, Randomized, Double-Blind, Active and Placebo Controlled Study. Clinical Therapeutics 31 (2): 260–71.
- ↑ Kleinert, R.; Lange, C.; Steup, A.; Black, P.; Goldberg, J.; Dejardins, P. (2008). Single Dose Analgesic Efficacy of Tapentadol in Postsurgical Dental Pain: The Results of a Randomized, Double-Blind, Placebo-Controlled Study. Anesthesia and Analgesia 107 (6): 2048–55.
- ↑ Medscape-Nucynta.
- ↑ (2010). NCBI Nucynta. Pharmacy and Therapeutics 35 (6): 330–357.
- ↑ emedtv-Nucynta.
- ↑ Nucynta.com D&A.
- ↑ Nucynta.com D&A.
- ↑ Mary G. McMasters, MD, FASAM. Universal Precautions for Prescribing Controlled Substances.
- ↑ Expert Committee on Drug Dependence. Tapentadol Pre-Review Report.
- ↑ Progressive Friday Fast Facts.
- ↑ Nucynta Savings Card.
- ↑ Nucynta.com-Mechanism of Action.
- ↑ Vlessides, M. (September 2006). Two New Analgesics May Help Patients After Bunionectomy. Anesthesiology News 32 (9). ID 5326.
- ↑ Nucynta. Nucynta.com. URL accessed on 2012-12-08.
- ↑ 25.0 25.1 (2012). rxlist.com. rxlist.com.
- ↑ 26.0 26.1 Nucynta vs Morphine Sulfate, a side effect and efficacy comparison for a male patient aged 38.
- ↑ Nucynta Related Hallucination.
- ↑ Nossaman, V. E.; Ramadhyani, U.; Kadowitz, P. J.; Nossaman, B. D. (2010). Advances in Perioperative Pain Management: Use of Medications with Dual Analgesic Mechanisms, Tramadol & Tapentadol. Anesthesiology Clinics 28 (4): 647–66.
- ↑ 29.00 29.01 29.02 29.03 29.04 29.05 29.06 29.07 29.08 29.09 29.10 Nucynta. Nucynta.com.
- ↑ Tapentadol Pregnancy and Breastfeeing Warnings.
- ↑ Leonhart, M. M., Deputy Administrator, Drug Enforcement Administration (May 2009). Schedules of Controlled Substances: Placement of Tapentadol Into Schedule II. Federal Register 74 (97): 23790–93.
- ↑ DEA Diversion Control - Controlled Substances Schedules. US Federal Government. URL accessed on 2012-05-16.
- ↑ Nucynta - Abuse Potential Section. Nucynta.com. URL accessed on 2012-05-16.
- ↑ Error on call to template:cite web: Parameters url and title must be specified Merigian KS, Blaho K..
External links[]
- PR Newswire: Phase II Data Show Efficacy and Tolerability of Tapentadol
- Nucynta dosing guide
- Nucynta dosing guide - special populations
Analgesics (N02A, N02B) | |
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Opioids |
Buprenorphine, Butorphanol, Codeine, Dextropropoxyphene, Diamorphine, Dihydrocodeine, Fentanyl, Hydrocodone, Hydromorphone, Ketobemidone, Levorphanol, Methadone, Morphine, Nicomorphine, Opium, Oxycodone, Oxymorphone, Pethidine, Tramadol, Tapentadol |
Salicylic acid and derivatives |
Aspirin (Acetylsalicylic Acid), Diflunisal, Ethenzamide, Salicin, Salicylamide · See also: NSAIDs |
Pyrazolones |
Aminophenazone, Metamizole, Phenazone |
Cannabinoids |
Cannabis, Tetrahydrocannabinol, AM404 |
Anilides |
Paracetamol (acetaminophen), Phenacetin |
Others |
Ziconotide, Ibuprofen, Ketoprofen, Mefenamic Acid, Naproxen, Diclofenac, Flurbiprofen, Diflunisal, Indomethacin, Ketorolac, Meloxicam, Piroxicam |
Adrenergics | ||||||||||||||||||||||||||
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Opioids edit |
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{Alfentanil} {Buprenorphine} {Carfentanil} {Codeine} {Codeinone} {Dextropropoxyphene} {Diamorphine (Heroin)} {Dihydrocodeine} {Fentanyl} {Hydrocodone} {Hydromorphone} {Methadone} {Morphine} {Morphinone} {Oxycodone} {Oxymorphone} {Pethidine (Meperidine)} {Remifentanil} {Sufentanil} {Tramadol} |
Template:Sigmaergics