oxycodone

Oxycodone
Systematic (IUPAC) name
4,5α-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one
Identifiers
CAS number	76-42-6
ATC code	N02AA05 N02AA55 (in combinations)
PubChem	5284603
DrugBank	APRD00387
ChemSpider	4447649
Chemical data
Formula	C18H21NO4
Mol. mass	315.364 g/mol
SMILES	eMolecules & PubChem
Synonyms	dihydrohydroxycodeinone, 14-hydroxydihydrocodeinone, 6-deoxy-7,8-dihydro-14-hydroxy-3-O-methyl-6-oxomorphine[1]
Pharmacokinetic data
Bioavailability	Up to 87%
Protein binding	45%
Metabolism	Hepatic (CYP450: 2D6 substrate)
Half life	3 - 4.5 hr
Excretion	Urine (19% unchanged)
Therapeutic considerations
Pregnancy cat.	B/D (prolonged use or in high doses at term)
Legal status	Controlled (S8)(AU) Schedule I(CA) Class A(UK) Schedule II(US)
Dependence Liability	Moderate - High
Routes	oral, intramuscular, intravenous, intranasal, subcutaneous, transdermal, rectal, epidural[2]
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Oxycodone is an opioid analgesic medication synthesized from opium-derived thebaine. It was developed in 1916 in Germany, as one of several new semi-synthetic opioids in an attempt to improve on the existing opiates and opioids: morphine, diacetylmorphine (heroin), and codeine.^[2]

Currently it is best known as the main active ingredient in a number of oral medications commonly prescribed for the relief of moderate to severe pain. Oxycodone can be combined with inert binders (e.g., OxyContin, Roxicodone, OxyIR); with paracetamol, also known as acetaminophen (e.g., Percocet, Endocet, Tylox, Roxicet); with aspirin (e.g., Percodan, Endodan, Roxiprin); and with ibuprofen (Combunox). Of the oral medications containing oxycodone, OxyContin is notable for its sales; for controversies concerning its patent status and marketing; and for its potentials for hazardous use, harmful use, dependence, and diversion.

Chemistry and nomenclature

Oxycodone's chemical name is derived from codeine. The chemical structures are very similar, differing only in that

• Oxycodone has a hydroxyl group at carbon-14 (codeine has just a hydrogen in its place), hence oxycodone;
• Oxycodone has a 7,8-dihydro feature, whereas codeine has a double bond between those two carbons; and
• Oxycodone has a carbonyl group (as in ketones) in place of the hydroxyl group of codeine, hence the "-one" suffix.

It is also similar to hydrocodone, differing only in that it has a hydroxyl group at carbon-14.^[3]

The synonyms for oxycodone in the academic literature include "dihydrohydroxycodeinone",^[1][4][5] "Eucodal",^[4][5] "Eukodal",^[2][6] "14-hydroxydihydrocodeinone",^[1][4] and "Nucodan".^[4][5] In a UNESCO convention, the translations of "oxycodone" are oxycodone (French), oxicodona (Spanish), والأوآسيكودون (Arabic), 羟考酮 (Chinese), and оксикодон (Russian).^[7] The word "oxycodone" should not be confused with "oxandrolone", "oxazepam", "oxybutynin", "oxytocin", or "Roxanol".^[8]

History

Freund and Speyer of the University of Frankfurt in Germany first synthesized oxycodone from thebaine in 1916,^[9] a few years after the German pharmaceutical company Bayer had stopped the mass production of heroin due to hazardous use, harmful use, and dependence. It was hoped that a thebaine-derived drug would retain the analgesic effects of morphine and heroin with less dependence. To some extent this was achieved, as oxycodone does not have the same immediate effect as heroin or morphine nor does it last as long.

The first clinical use of the drug was documented in 1917.^[6] It was first introduced to the US market in May 1939.

The International Narcotics Control Board estimates that 11.5 tons^{[clarification needed]} of oxycodone were manufactured worldwide in 1998, which grew to 75.2 tons in 2007.^[10] Of all countries, the United States had the highest total consumption of oxycodone in 2007 (82% of the world total of 51.6 tons).^[10] In addition, in 2007 the U.S. had the highest per capita consumption of oxycodone, followed by Canada, Denmark, Australia, and Norway.^[10]

OxyContin

Oxycontin tablets of varying dosage

OxyContin is the brand name of a time-release formula of oxycodone produced by the pharmaceutical company Purdue Pharma.^[11] It was approved by the U.S. Food and Drug Administration in 1995 and first introduced to the U.S. market in 1996.^[11] By 2001, OxyContin was the best-selling non-generic narcotic pain reliever in the U.S.; in 2002, over 7.2 million prescriptions were written for it, for total sales of $1.5 billion.^[11] An analysis of data from the U.S. Drug Enforcement Administration found that retail sales of oxycodone "jumped nearly six-fold between 1997 and 2005."^[12] Mundipharma distributes OxyContin in Australia,^[13] China,^[14] and Europe.^[15]

OxyContin is available in 5 mg (blue) tablets in Canada and the U.K.; 10 mg (white) in Canada, the U.S., and the U.K.; 15 mg (grey) in the U.S.; 20 mg (pink) in Canada, the U.S., and the U.K.; 30 mg (brown) in the U.S.; 40 mg (tan) in Canada, the U.S., and the U.K.; 60 mg (red) in the U.S.; and 80 mg (green) in Canada, the U.S., and the U.K.^[16][17][18] In 2001, Purdue Pharma suspended distribution of 160 mg tablets in the U.S. because of the "possibility of illicit use of tablets of such high strength."^[11][19]

Slang terms for OxyContin include "Hillbilly Heroin", "Killers", "OC", "Oxy", "Oxycoffin", and "Oxycotton".^[20][21][22] The word "OxyContin" should not be confused with "morphine sulfate", "MS Contin", "Oxandrin", "oxybutynin", "oxytocin", or "Roxicodone".^[8][23] Among those names the final given, Roxicodone, being the same drug, Oxycodone, but IR rather than ER: "-contin" being Oxycodone continuous release or Extended Release. Roxicodone being Instant Release, or rapid (Rox(i)codone) release. This mistake may be a fatal one to casual users rather than users with high tolerances who may prefer the immediate release to even feel an effect, such as long term heroin addicts.

Lawsuits concerning generic OxyContin

Purdue has multiple patents for OxyContin, but has been involved in a series of ongoing legal battles on the validity of these patents. On June 7, 2005, the United States Court of Appeals for the Federal Circuit upheld a decision from the previous year that some of Purdue’s patents for OxyContin could not be enforced.^[24] This decision allowed and led to the immediate announcement from Endo Pharmaceuticals that they would begin launching a generic version of all four strengths of OxyContin.^[25] Purdue, however, had already made negotiations with another pharmaceutical company (IVAX Pharmaceuticals) to distribute their brand OxyContin in a generic form.^[25] This contract was severed, and as of October 2005 Watson Pharmaceuticals became the exclusive U.S. distributor of Purdue-manufactured generic versions of OxyContin tablets in 10-, 20-, 40-, and 80-milligram dosages.^[26]

On February 1, 2006, the Federal Circuit Court of Appeals issued a decision revising its June 7, 2005, decision.^[27] This time the court vacated the lower court's "judgment that the patents-in-suit are unenforceable due to inequitable conduct," and the case was "remanded for further proceedings."^[27]

Purdue Pharma has since announced resolution of its infringement suits with Endo,^[28] Teva,^[29] IMPAX,^[30] and Mallinckrodt.^[31] Endo and Teva each agreed to cease selling generic forms of OxyContin.^[28][29] IMPAX negotiated a temporary, and potentially renewable, license.^[30] In 2008, Mallinckrodt Pharmaceuticals reintroduced generic OxyContin in the strengths of 10 mg, 20 mg, 40 mg and 80 mg, which was made possible by a temporary royalties-bearing license with Purdue Pharma that expires in 2009.^[31]

Marketing and misbranding

Critics have accused Purdue Pharma of putting profits ahead of public interest by applying "significant political pressure" to attempt to reverse South Carolina's requiring prior approval before a person with Medicaid can receive the drug;^[32] for "fail[ing] to adequately warn consumers of the risks" of OxyContin such as dependence;^[33] and for promoting the drug "aggressively" and by means such as "promotional beach hats, pedometers and swing-music CDs."^[33][34]

In May 2007 Purdue Pharma "agreed to pay $19.5 million" in fines relating to aggressive off-label marketing practices of OxyContin in 26 states and the District of Columbia.^[35] In specific, the company encouraged dosing more frequent than the recommended interval of 12 hours, and did not fully disclose the risk of hazardous or harmful use.^[35]

Later in May 2007 Purdue Pharma and three of its top executives pleaded guilty in a Virginia federal court to charges that they misbranded OxyContin by representing it to have "less euphoric effect and less abuse potential" than it actually has, and by claiming that people taking the drug at low doses could stop taking it suddenly without symptoms of withdrawal.^[36] The FDA had not approved these claims.^[37] The company and the executives were to pay $634 million in fines for felony and misdemeanor misbranding.^[36]

In October 2007, officials in Kentucky filed a lawsuit against Purdue Pharma for misleading health care providers and consumers "regarding the appropriate uses, risks and safety of OxyContin"; as of mid-2008, however, the case had been "consolidated with other lawsuits into a single multi-litigation suit" in a federal court in New York.^[38]

Other preparations

Formulations containing oxycodone and other analgesics.

Oxy·IR immediate-release oxycodone tablets from Purdue Pharma in Canada are available in 5, 10, and 20 mg strengths.^[17]

OxyNorm is available in 5, 10, and 20 mg capsules, and also as a 5 mg/5 ml liquid in 250 ml bottles in Australia, New Zealand, and the U.K.^[39][40][41] In addition, OxyNorm is available in a 10 mg/ml liquid concentrate for oral use in the U.K., and in a 10 mg/ml solution for injection or infusion in New Zealand and the U.K.^[41][42]

Percocet (oxycodone with paracetamol/acetaminophen) tablets are available in the U.S. with 2.5, 5, 7.5, and 10 mg of oxycodone and varying amounts of acetaminophen.^[43]

Depalgos (oxycodone with paracetamol) tablets are marketed in Italy, with 325mg Paracetamol and 5, 10, and 20mg oxycodone. Recent legislation in Italy has made it easier for physicians to prescribe this medication and other opioids to pain patients.^[44]

Percodan tablets available in the U.S. contain 4.8355 mg of oxycodone HCl and 325 mg of aspirin.^[45]

Proladone suppositories, available in Australia, contain 30 mg of oxycodone pectinate.^[46]

Injectable oxycodone hydrochloride or tartrate is available in ampoules and multi-dose vials in many European countries and to a lesser extent various places in the Pacific Rim. For this purpose, the most common trade names are Eukodol and Eucodol. The German-language package insert for an oxycodone injectable indicates that the preferred route of injection is intramuscular.

Roxicodone, a generic oxycodone product designed to have an immediate release effect for rapid pain relief, is available in 5 mg (white), 15 mg (green), and 30 mg (blue) tablets; in a 5 mg per 5 ml oral solution; and in a 20 mg per ml liquid concentrate.^[47][48] On March 31, 2009, the U.S. Food and Drug Administration directed Boehringer Ingelheim Roxane and Xanodyne Pharmaceuticals to cease manufacture and distribution of 5 mg Roxicodone tablets in the U.S. because they lacked proper approval.^[49]

Targin is a tablet with a prolonged-release oxycodone/naloxone combination.

Clinical use

In a 2008 review written by authors who "are members of advisory boards and speaker panels for Mundipharma," prolonged-release oxycodone (i.e., OxyContin) was found to be superior to placebo in randomized controlled trials concerning diabetic neuropathy, postherpetic neuralgia, osteoarthritis, ambulatory laparoscopic tubal ligation surgery, unilateral total knee arthroplasty, and abdominal/gynaecological surgery.^[50]

In 2001, the European Association for Palliative Care recommended that oral hydromorphone or oxycodone, "if available in both normal release and modified release formulations for oral administration," be second-line alternatives to oral morphine for cancer pain.^[51] There is no evidence that any opioids are superior to morphine in relieving the pain of cancer, and no controlled trials have shown oxycodone to be superior to morphine.^[52] However, switching to an alternative opioid can be useful if adverse effects are troublesome, although the switch can be in either direction, i.e. some patients have fewer adverse effects on switching from morphine to oxycodone and vice versa.

Pharmacology

Mechanism of action

A group of Australian researchers has proposed (based on a 1997 study in rats) that oxycodone, unlike morphine (the effect of which is mediated by μ-opioid receptors), acts on κ-opioid receptors.^[53] Further research by this group indicates the drug appears to be a κ_2b-opioid agonist.^[54] However, this has been disputed, primarily on the basis that oxycodone produces effects typical of μ-opioid agonists.^[55]

Research by a Japanese group suggests that the effect of oxycodone is mediated by different receptors in different situations. Specifically, in diabetic mice the κ-opioid receptor appears to be involved in the antinociceptive effects of oxycodone,^[56] while in non-diabetic mice the μ₁-opioid receptor seems to be primarily responsible for these effects.^[57]

Absorption

After a dose of conventional oral oxycodone, peak plasma levels of the drug are attained in approximately one hour;^[58] in contrast, after a dose of OxyContin (an oral continuous release formulation), peak plasma levels of oxycodone occur in about three hours.^[16]

Distribution

Oxycodone in the blood is distributed to skeletal muscle, liver, intestinal tract, lungs, spleen, and brain.^[16] Conventional oral preparations of oxycodone start to reduce pain within 10–15 minutes; in contrast, OxyContin starts to reduce pain within 1 hour.^[3]

Metabolism

Oxycodone is metabolized to α and β oxycodol; oxymorphone, then α and β oxymorphol and noroxymorphone; and noroxycodone, then α and β noroxycodol and noroxymorphone (N-desmethyloxycodone).^[58] These metabolites are true only for humans.^[59] As many as six metabolites for oxycodone (14-hydroxydihydromorphinone, 14-hydroxydihydrocodeine, 14-hydroxydihydrocodeinone N-oxide {oxycodone N-oxide}, 14-hydroxydihydroisocodeine, 14-hydroxydihydrocodeine N-oxide, and noroxycodone) have been found in rabbits.^[60] A study using conventional oral oxycodone concluded that oxycodone itself, and not its metabolites, is responsible for the drug's opioid effects on the brain.^[58]

Unlike morphine and hydromorphone, oxycodone is metabolized by the cytochrome P450 enzyme system in the liver, making it vulnerable to drug interactions.^[16] Some people are fast metabolizers resulting in reduced analgesic effect but increased adverse effects, while others are slow metabolisers resulting in increased toxicity without improved analgesia.^[61][62] The dose of OxyContin must be reduced in patients with reduced hepatic function.^[3]

Elimination

Oxycodone and its metabolites are mainly excreted in the urine and sweat; therefore, it accumulates in patients with renal impairment.^[3]

Dosage and administration

Oxycodone can be administered orally, intranasally, via intravenous/intramuscular/subcutaneous injection or rectally. The bioavailability of oral administration averages 60–87%, with rectal administration yielding the same results; intranasal varies between individuals with a mean of 46%^[63].

Oxycodone is approximately 1.5–2 times as potent as morphine when administered orally.^[64][65] However, 10–15 mg of oxycodone produces an analgesic effect similar to 10 mg of morphine when administered intramuscularly.^[66] Therefore, as a parenteral dose, morphine is approximately up to 50% more potent than oxycodone.

There are no comparative trials showing that oxycodone is more effective than any other opioid. In palliative care, morphine remains the gold standard;^[52] however, oxycodone can be useful as an alternative opioid if a patient has troublesome adverse effects with morphine.

Notable tentative / obsolete

In 1954, William S. Burroughs wrote to Allen Ginsberg claiming certain experts, from as early as the beginning of the 1930s, maintained that the "oxygen bridge" on the oxycodone molecule added "cocaine-like" effects to its profile.^[67]

Side effects

Main side effects of oxycodone

The most commonly reported effects include constipation, fatigue, dizziness, nausea, lightheadedness, headache, dry mouth, anxiety, pruritus, euphoria, and diaphoresis.^[68] It has also been claimed to cause dimness in vision due to miosis. Some patients have also experienced loss of appetite, nervousness, abdominal pain, diarrhea, ischuria, dyspnea, and hiccups,^[16] although these symptoms appear in less than 5% of patients taking oxycodone. Rarely, the drug can cause impotence, enlarged prostate gland, and decreased testosterone secretion.^[69]

In high doses, overdoses, or in patients not tolerant to opiates, oxycodone can cause shallow breathing, bradycardia, cold, clammy skin, apnea, hypotension, miosis (pupil constriction), circulatory collapse, respiratory arrest, and death.^[16]

Withdrawal related side effects

There is a high risk of experiencing severe withdrawal symptoms if a patient discontinues oxycodone abruptly. Therefore therapy should be gradually discontinued rather than abruptly discontinued. People who use oxycodone in a hazardous or harmful fashion are at even higher risk of severe withdrawal symptoms as they tend to use higher than prescribed doses. The symptoms of oxycodone withdrawal are the same as for other opiate based painkillers and may include "anxiety, nausea, insomnia, muscle pain, muscle weakness, fevers, and other flu like symptoms."^[20]

Withdrawal symptoms have also been reported in a newborn whose mother had been either injecting OxyContin or orally taking percocet during pregnancy.^[70]

Hazardous use, harmful use, dependence, and diversion

United States

Instances of hazardous use, harmful use, and diversion of OxyContin have increased in the U.S. beginning in the late 1990s.^[71] The slang term hillbilly heroin for OxyContin refers to the occurrence of the "earliest reported cases of Oxycontin abuse" in the U.S. in rural areas such as Appalachia.^[72] Diversion of OxyContin in the U.S. may occur through "fraudulent prescriptions, doctor shopping, over-prescribing, and pharmacy theft."^[71]

A 2003 study by the Government Accountability Office found four factors that may have contributed to hazardous use, harmful use, and diversion of OxyContin in the U.S.:^[11]

• OxyContin contains a large amount of oxycodone compared with other types of oxycodone-containing pills.
• OxyContin's warning label said to not crush the controlled-release tablets because of the potential for rapid release of oxycodone, which led to many people crushing the tablets and injecting or snorting the drug.
• By 2001, sales of OxyContin in the U.S. exceeded $1 billion per year.
• People who received prescriptions for OxyContin and lived in poor areas of Appalachia may have perceived a "profit potential" in selling the pills to drug dealers (e.g., 20 mg of OxyContin could be bought for $2 but sold for $20).

A study published in 2005 examined the prevalence of hazardous or harmful use of opiate analgesics among "recreational drug users and street addicts" as perceived by "key informants" throughout the U.S.; the authors found that hazardous or harmful use of opiates was increasing in general, but that of the drugs studied hazardous or harmful use of OxyContin "was mentioned most frequently."^[73] Purdue Pharma has attempted to reformulate the 10–40 mg strengths of OxyContin to prevent the release of a high percentage of the oxycodone by crushing; however, in 2008 a joint panel convened by the U.S. Food and Drug Administration was "concerned that abusers could find a way to manipulate the new formulation."^[74]

Other countries

The illegal use of OxyContin began in Australia in the early 2000s partly because the government's Pharmaceutical Benefits Scheme subsidises the drug.^[22][75] By 2007, 51% of a national sample of injection drug users in Australia had reported using oxycodone, and 27% had injected it in the last six months.^[76]

Hazardous use, harmful use, and diversion of OxyContin in the U.K. commenced in the early- to mid-2000s.^[77] The first known death due to OxyContin overdose in the U.K. occurred in 2002.^[78]

Animal studies

Research has shown that the brains of adolescent mice, which were exposed to OxyContin, can sustain lifelong and permanent changes in their reward system.^[79][80] It is notable that the vast majority of OxyContin related deaths are attributed to ingesting substantial quantities of oxycodone in combination with another depressant of the central nervous system such as alcohol, barbiturates and related drugs.^[81]

Conventions and national laws

Oxycodone is subject to international conventions on narcotic drugs. In addition, oxycodone is subject to national laws that differ by country.

International

The 1931 Convention for Limiting the Manufacture and Regulating the Distribution of Narcotic Drugs of the League of Nations included oxycodone (but incorrectly called it "dihydrohydrooxycodeinone" instead of "dihydrohydroxycodeinone").^[82] The 1961 Single Convention on Narcotic Drugs of the United Nations, which replaced the 1931 convention, categorized oxycodone in Schedule I.^[83] Global restrictions on Schedule I drugs include "limit[ing] exclusively to medical and scientific purposes the production, manufacture, export, import, distribution of, trade in, use and possession of" these drugs; "requir[ing] medical prescriptions for the supply or dispensation of [these] drugs to individuals"; and "prevent[ing] the accumulation" of quantities of these drugs "in excess of those required for the normal conduct of business."^[83]

Australia

Oxycodone is in Schedule I (derived from the Single Convention on Narcotic Drugs) of the Commonwealth's Narcotic Drugs Act 1967.^[84] In addition, it is in Schedule 8 of the Australian Standard for the Uniform Scheduling of Drugs and Poisons ("Poisons Standard"), meaning that it is a "controlled drug... which should be available for use but require[s] restriction of manufacture, supply, distribution, possession and use to reduce abuse, misuse and physical or psychological dependence."^[85]

Canada

Oxycodone is a controlled substance under Schedule I of the Controlled Drugs and Substances Act (CDSA).^[86] Every person who seeks or obtains from a practitioner either the substance or an authorization to obtain the substance must disclose to that practitioner information on all controlled substances and authorizations for controlled substances obtained from any other practitioner within the preceding 30 days; otherwise, the person may be found "guilty of an indictable offence and liable to imprisonment for a term not exceeding seven years".^[86] Anyone possessing the substance for the purpose of trafficking "is guilty of an indictable offence and liable to imprisonment for life".^[86]

Germany

The drug is in Appendix III of the Narcotics Act ("Betäubungsmittelgesetz" or BtMG).^[87] The law states that only physicians, dentists and veterinarians ("Ärzte, Zahnärzte und Tierärzte") can prescribe oxycodone, and that the federal government can regulate the prescriptions (e.g., by requiring reporting).^[87]

Hong Kong

Oxycodone is regulated under Part I of Schedule 1 of Hong Kong's Chapter 134 Dangerous Drugs Ordinance.^[88] The penalty for trafficking (Section 4) or manufacturing (Section 6) the substance is a $5,000,000 HKD fine and/or life imprisonment.^[88] In Section 8 of the Ordinance, possession of the substance for consumption without licence from the Department of Health is illegal and subject to a $1,000,000 HKD fine and/or 7 years of imprisonment.^[88] Per Sections 22-23, only specific health professionals and others (e.g., "a person in charge of a laboratory used for the purposes of research") may possess and supply the substance.^[88] Anyone who supplies the substance without a valid prescription can be fined $10,000 HKD according to Section 31.^[88]

United Kingdom

Oxycodone is a Class A drug under the Misuse of Drugs Act.^[89] For Class A drugs, which are "considered to be the most likely to cause harm," possession without a prescription is punishable by up to seven years in prison, an unlimited fine, or both.^[90] Dealing of the drug illegally is punishable by up to life imprisonment, an unlimited fine, or both.^[90] In addition, oxycodone is a Schedule 2 drug per the Misuse of Drugs Regulations 2001 which "provide certain exemptions from the provisions of the Misuse of Drugs Act 1971."^[91]

United States

Under the Controlled Substances Act, oxycodone is a Schedule II drug because it "has a high potential for abuse," because it "has a currently accepted medical use in treatment in the United States or a currently accepted medical use with severe restrictions," and because use of the drug "may lead to severe psychological or physical dependence."^[92] According to Section 829 of the Act, Schedule II drugs must be dispensed only with the written prescription of a practitioner except in certain situations (e.g., "dispensed directly by a practitioner, other than a pharmacist," or "dispensed upon oral prescription (i.e. telephone)" in "emergency situations").^[92] Furthermore, Section 829 specifies that prescriptions for Schedule II drugs cannot be refilled.^[92]

See also

• Illegal drug trade
• List of drug-related deaths
• Psychoactive drug
• Recreational drug use

Notes

References

Further reading

• Meier, Barry (2003). Pain killer: a "wonder" drug's trail of addiction and death. Emmaus, PA: Rodale. ISBN 1579546382. 
• Pinsky, Drew (2004). When painkillers become dangerous: what everyone needs to know about OxyContin and other prescription drugs. Center City, MN: Hazelden. ISBN 159285107X. 
• Lockwood, Brad (2006). Oxycontin: from pain relief to addiction. New York: Rosen Pub. Group, Inc. ISBN 9781404209138. 

External links

• Coluzzi F, Mattia C. Oxycodone. Pharmacological profile and clinical data in chronic pain management. Minerva Anestesiol 2005 Jul-Aug;71(7-8):451-60.
• Rosenberg T. When is a pain doctor a drug pusher? New York Times 2007 Jun 17.
• Deadly combinations. St. Petersburg Times 2008 Feb 17 - May 19.

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