INTRODUCTION
Methadone is a synthetic opioid that was developed as an analgesic by German scientists during World War II. It has been used as part of the treatment for opioid addicted patients since the 1960s. More recently, methadone has been used as an analgesic for the management of various chronic pain conditions.
Methadone’s special pharmacologic properties makes it effective in the treatment of addiction because it prevents withdrawal symptoms, reduces cravings for opioids, and blocks the euphoric effect of other opioids if they are used concurrently. Methadone’s long half-life means that it needs to be taken only once a day to accomplish these goals. The complexity of methadone’s pharmacology is also a cause of concern. High inter-individual variability, multiple drug interactions, the risk of overdose and other adverse events pose many challenges to clinicians.
Between 1996 and 2001 in Ontario, the number of patients involved in methadone maintenance therapy increased from 1,595 to 7,7871. Quite clearly the abuse of narcotics is on the rise. The number of patients on methadone in 2011 is likely significantly higher, with 1,150 patients in Thunder Bay alone. As a result, the general dental practitioner may have an increasing proportion of these patients in their practice. It is important that dentists be aware of the potential difficulties that may be encountered when treating patients receiving methadone.
In Canada, methadone is a controlled substance, only prescribed by physicians with an exemption under section 56 of the Controlled Drugs and Substances Act, and in most provinces, these exemptions are granted under federal authority by the Office of Controlled Substances.2 The pharmacy dispenses a single daily oral dose mixed with orange juice or flavoured syrup to deter use via the parenteral route. Dosages are titrated to the individual, and range from 50 to 100 mg per day.3
PHARMACOLOGY
Methadone is a strong agonist of the mu receptor. This mu receptor activity is believed to account for the majority of methadone’s analgesic effects, as well as respiratory depression, physical dependence, miosis, and decreased GI motility. Methadone is also a non-competitive antagonist of the NMDA (N-methyl-D-aspartate) receptor, which is believed to prevent the development of opioid tolerance, and may be linked to pain processing and spinal neural plasticity, and hence its utility in treatment of chronic pain.4,5
Methadone is lipid soluble and highly bound to plasma proteins, forming stores of drug that are slowly released in the blood stream as active free methadone. It is well absorbed, has a rapid onset (30 minutes) and the analgesic effects will typically last for 4-8 hours and may prevent opioid withdrawal symptoms or craving for 24-36 hours.6,7
The clearance rate is highly variable with the half-life ranging from 12 to 100 hours.8 Factors such as fat stores, urine pH, plasma protein expression, levels of metabolic enzymes, competitive binding for plasma protein and metabolic enzymes or enzyme genetic variation can lead to substantial variable clearance rates between individuals and within an individual over time.4 Shorter than expected clearance rates can lead to lack of analgesic efficacy and withdrawal symptoms, and longer than expected clearance rates can lead to toxicity and potentially fatal overdoses.4 Thus determination of an appropriate methadone dose is a highly individualized process.
Methadone is principally eliminated by metabolism via the cytochrome enzyme system in the liver. The main enzymes are CYP3A4, CYP2B6 and to a minor extent CYP2D6. It is then excreted in the feces and urine.
DRUG INTERACTIONS
Drug interactions can occur through several mechanisms. Many interactions related to methadone involve the induction or inhibition of the major hepatic cytochrome enzymes, in particular CYP3A4.9 Drugs like carbamazepine, HIV antiretrovirals and St. John’s Wort can induce CYP3A4 leading to lower methadone levels and lack of analgesic efficacy and withdrawal symptoms.9 Erythromycin, ciprofloxacin, clarithromycin, fluconazole and grapefruit juice can inhibit the CYP3A4 enzyme leading to elevated serum methadone levels and potential toxicity.6 Interactions may also occur independently of the cytochrome system.
Certain plasma proteins levels can be altered by concurrent administration of medications or by systemic diseases such as cancer. Medications such as propranolol and imipramine compete for protein binding sites, and elevate the plasma level of methadone.4 Pharmacodynamic interactions can result when drugs of similar pharmacologic effects are given concurrently. Benzodiazepines such as diazepam and antihistamines such as Benadryl can lead to significant CNS depression and decreased respiratory drive.9 While knowledge of drug interactions may aid in drug selection, the fact that a drug interaction may occur should not exclude its use. Not all patients will develop drug interactions. These occurrences are related to doses of medications, clinical pharmacology of the drug(s), and variable individual genetics that determine CYP450 enzyme activity.9
MEDICAL AND DENTAL IMPLICATIONS
Substance abuse patients often have low expectations of healthcare and may have experienced difficulty in accessing medical and dental services. Chaotic lifestyles associated with substance misuse do not favour regular dental or medical care, and many patients have a poor standard of general health as a result.
Mental illness, depression and anxiety are very common in opioid-dependent patients, with a lifetime rate of up to 50% has been reported in this population.10 Substance abusers are more likely to experience dental anxiety. This may be because many patients with substance abuse problems have not previously sought regular dental care, tending to attend only when in pain. Often the analgesic effects of the narcotics have masked dental pain and patients may have extensive dental disease upon presentation, necessitating careful planning. Clinicians need to be aware that this group of patients tends to have higher rates of hepatitis B and C virus infection as well as HIV infection due to needle sharing with heroin use. In the US, HCV infection is estimated to be approximately 33% of injection drug users.11
Approximately 25% of all new HIV infection cases are also injection drug users, the majority of them are addicted to heroin.12 Patients with heroin abuse may also have a history of infective endocarditis, thrombocytopenia and clotting disorders due to liver disease.13,14 Methadone users may also have a prolonged Q-T interval that can predispose patients to life-threatening cardiac arrhythmias, especially when high doses of methadone are used in association with other risk factors such as HIV infection and concurrent use of CYP450 inhibitors.15 Consultation with the patients’ medical practitioner would be prudent prior to performing dental and oral surgical procedures.
Patients on methadone tend to have high caries and periodontal disease rates.16,17 A number of factors are at play. Generally, opiate abusers tend to have a poor oral hygiene and poor nutritional intake leading to increased dental disease. Individuals with drug addiction tend to have a diet high in carbohydrates as economic factors may encourage the consumption of convenience foods6 and some literature suggests that methadone patients as well as active opiate addicts tend to consume increased amounts of refined sugars than the rest of the population.18
Methadone, as well as other opiates, produces xerostomia, which further compounds the problem of plaque retention. Methadone formulations may contain very high levels of sugar and users are known to retain the syrup in their mouth in order to prolong the absorption time3 or for regurgitating it later for sale or injection.19 The pattern of caries in patients with a history of opiate use is generally cervical
caries and such lesions can be very difficult to restore. The high acid content of methadone makes erosion a risk. It is not advisable for patients using methadone to brush their teeth immediately after their dose as this increases risk of chemical erosion.6
Use of a straw for ingestion of methadone should be recommended to minimize contact with dental structures.6 Pain management is also an issue with these patients. Non-steroidal anti-inflammatories (NSAID’s) are the main pain medication to be prescribed, although narcotics with high mu receptor affinity, such as hydromorphone can be used. It is recommended to have the physician monitoring the methadone therapy to manage/prescribe narcotic analgesics20.
When these patients finally present to the dental office, oral disease may be very advanced and extensive. Realistic treatment planning instead of heroic attempts to maintain heavily damaged teeth may be more appropriate.3 A focused preventive regimen is indicated with emphasis on the use of sugar-free methadone, oral hygiene instruction, dietary counselling, the use of fluoridated tooth-pastes and mouthwashes as well as topical fluoride treatments when indicated.3,6 Anxiety management and good communication are important in this patient population.
The dental management of patients receiving methadone treatments can be complex. There are a variety of drug related issues as well as medical and psychosocial issues that need to be considered prior to initiating dental treatment. Consultation with the patient’s physician regarding their medical history is recommended, especially when narcotic analgesics need to be prescribed.OH
Robert Green, DDS , MD, MSc, FRCD(C) is on staff at Hamilton Health Sciences and private practice in Stoney Creek, ON.
Bruce R. Pynn, MSc, DDS, FRCD(C) is Oral Health’s editorial board member for oral surgery.
Oral Health welcomes this original article.
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