Dipipanone

Dipipanone (Pipadone)[2] is a strong opioid analgesic drug, used for very severe pain in cases where other analgesics are unsuitable, for instance where morphine is indicated but cannot be used due to the patient being allergic to morphine.

Dipipanone

Clinical data
Trade names	Diconal
Routes of administration	Oral
ATC code	none
Legal status
Legal status	AU: S8 (Controlled drug) CA: Schedule I DE: Anlage I (Authorized scientific use only) UK: Class A US: Schedule I
Pharmacokinetic data
Metabolism	Liver-mediated
Elimination half-life	3.5 hours[1]
Identifiers
IUPAC name 4,4-diphenyl-6-(1-piperidinyl)-heptan-3-one
CAS Number	467-83-4^N
PubChem CID	13331
DrugBank	DB01491^Y
ChemSpider	12766^Y
UNII	X188638Y2V
CompTox Dashboard (EPA)	DTXSID50894759
ECHA InfoCard	100.006.728
Chemical and physical data
Formula	C24H31NO
Molar mass	349.52 g·mol^−1
3D model (JSmol)	Interactive image
SMILES O=C(CC)C(C1=CC=CC=C1)(CC(C)N2CCCCC2)C3=CC=CC=C3
InChI InChI=1S/C24H31NO/c1-3-23(26)24(21-13-7-4-8-14-21,22-15-9-5-10-16-22)19-20(2)25-17-11-6-12-18-25/h4-5,7-10,13-16,20H,3,6,11-12,17-19H2,1-2H3^Y Key:SVDHSZFEQYXRDC-UHFFFAOYSA-N^Y
^NY (what is this?)  (verify)

Dosage forms

The main preparation of the drug commercially available is mixed with cyclizine (Diconal, Wellconal) which has the advantage of reducing nausea, vomiting and histamine release associated with strong opioid therapy.[3]

Dipipanone was also available as an oral mixture 10 mg/5ml without the cyclizine during the 1970s–1980s in the United Kingdom. This form was rare and used normally only in drug trials and in specialist Diconal addiction clinics.

With the exception of oxycodone, dipipanone is now the only alternative opioid left to use in the UK that is of equal strength to morphine that can be prescribed instead.

One of the biggest disadvantages of using dipipanone is that it is only produced in one dosage form that is mixed with the anti-emetic cyclizine at a ratio of 25% dipipanone to 75% cyclizine which limits the dose of dipipanone to an absolute maximum of 3 tablets per dose up to 4-6 times a day.

As of November 2011 Amdipharm stopped making the Diconal brand tablets for the UK due to undisclosed commercial reasons. However the product is listed as available on the manufacturer's website as of July 1, 2014.[4] General practitioners are now advised to prescribe it as generic dipipanone/cyclizine tablets.

Use

Dipipanone is now unavailable in most countries of the world either by laws prohibiting its medicinal use as in the United States or by falling out of production as more modern analgesics took its market share. Great Britain, Northern Ireland and South Africa are known to continue to use the substance but it is infrequently prescribed.

Dipipanone is a Schedule I controlled substance in the United States; it has been assigned the ACSCN of 9622 and in 2013 had an annual manufacturing quota of 5 g.[5]

Chemistry

Chemically, dipipanone belongs to the class of opioids called the 4,4-diphenylheptane-3-ones. It closely resembles methadone, the only structural difference being the N,N-dimethyl moiety of methadone being replaced with a piperidine ring. Other related compounds with equivalent activity where the piperidine ring has been replaced by other groups, include the morpholine derivative phenadoxone, as well as the corresponding pyrrolidine derivative.[6] The synthesis is the same as for phenadoxone, with the exception that piperidine is used in lieu of morpholine.[7]

Pyrrolidine homologue of dipipanone, CAS# 60996-94-3

Medical and recreational use

Prescription of dipipanone is discouraged apart from in exceptional circumstances, because of the perceived risk of abuse - the BNF marks the substance as "less suitable for prescribing" along with other older compounds such as pethidine and pentazocine with unusual abuse patterns. The combination with cyclizine leads to a very strong "rush" if the drug is injected, however the tablets contain insoluble binders which led to many limb amputations and some fatalities (as with temazepam). During the late 1970s to early 1980s in the UK, many deaths were blamed on misuse of this preparation. As supplies became unavailable, opiate users would mix crushed methadone tablets or ampoules with crushed cyclizine tablets, in an attempt to replicate the effect of Diconal.

References

1. Paterson S (April 1992). "Pharmacokinetics of dipipanone after a single oral dose". British Journal of Clinical Pharmacology. 33 (4): 449–50. doi:10.1111/j.1365-2125.1992.tb04066.x. PMC 1381337. PMID 1349495.
2. GB patent 654975, Peter Ofner, Eric Walton, "Improvements relating to the Synthesis of Diphenyl Ketones", published 1948-02-09, issued 1951-07-04
3. Fang J, Glover V, Jarman J, Gorrod JW (1995). "Inhibition of monoamine oxidase B by dipipanone and cyclizine". Pharmaceutical Sciences. 1 (6): 295–296.
4. "Amdipharm Mercury Company Ltd". www.amcolimited.com/products/amdipharm-spc. Amdipharm Mercury Company Ltd. Retrieved 1 July 2014.
5. "Proposed Aggregate Production Quotas for Schedule I and II Controlled Substances and Proposed Assessment of Annual Needs for the List I Chemicals Ephedrine, Pseudoephedrine, and Phenylpropanolamine for 2014". Diversion Control Division. U.S. Department of Justice, Drug Enforcement Division.
6. Lenz GR, Evans SM, Walters DE, Hopfinger AJ (1986). Opiates. Academic Press. pp. 406–407. ISBN 978-0-12-443830-9.
7. Ofner P, Walton E (1950). "444. Search for new analgesics. Part IV. Variations in the basic side-chain of amidone". Journal of the Chemical Society (Resumed): 2158. doi:10.1039/JR9500002158.