David Overton, PA-C
Natural Medicines & Family Practice
1315 Ruddell Rd. SE Lacey, WA 360-357-8054

Chronic Pain Medicine, Part 1
What side effects do drugs for chronic pain have? Are there alternatives? For starters, we know that anti-inflammatory drugs can damage your stomach, kidneys, heart and liver. Acetaminophen (Tylenol) can damage the liver. What about opiates (narcotics), other pain medicines and antidepressants?
Opiates have some advantages. They work for pain and, while affected by the liver, they don’t damage it. Disadvantages include addiction, abuse, tolerance (meaning you need more), side effects and interactions with other medicines. Most people are aware psychiatric medicines work on serotonin, dopamine, norepinephrine, GABA, acetylcholine and other neurotransmitter receptors. Opiates work on different receptors that regulate neurotransmitters and the trick is to use a drug that has positive without intolerable negative effects. The opiate receptors include:
• Mu1 receptors relieve pain
• Mu2 receptors regulate sedation, sleep, itching, vomiting, urine retention, euphoria, drug dependence, constipation, histamine release (which affects the immune system, circulation and neurotransmitters) and pupil contraction.
• Kappa receptors regulate sedation, sleep, drug dependence, hormones (insulin, norepinephrine, thyroid, sex hormones, etc.), respiration and urine release.
• Delta receptors. It’s not known how opiates affect these.
• Sigma receptors regulate mood and cause anxiety, depression and other symptoms.
Opiate receptors in neurons are regulated via enzymes and electrolytes that have short term effects (relieve pain and/or cause side effects) or long term effects on your genetic codes. This is where some alternative supplements can be helpful and I would be concerned about long term opiate use on my genes and strive to find alternatives.
For example, morphine and it’s derivatives affect potassium, sodium, epinephrine and norepinephrine (adrenaline levels) and can turn off or turn on numerous cellular functions by affecting cyclic AMP (a chemical that interacts with ATP ). ATP regulates many aspects of cellular function, is a pain reliever all by itself and interacts with or controls serotonin, dopamine and other neurotransmitters. Ask for my articles on ATP and we have found alternative medicines that help here.
It’s believed that opiates block the release of acetylcholine, norepinephrine, serotonin and substance P (another neurotransmitter and pain chemical) to speed up or slow down cellular functions. This could cause diverse effects: anxiety or depression, more or less pain, having to urinate more or urinate less, insomnia or sedation, blood pressure goes up or down, constipation or irritable bowel and other problems. Individuals using opiates long term may require medical management of all these issues. There are alternative medicines to manage these problems if you must take opiates.
In addition, we have to consider affects on dopamine and GABA. These neurotransmitters regulate pain, mood and pleasurable activities. Here is where opiates are abused or cause addiction and there are alternatives to consider. In addition, dopamine and GABA affect sleep, mood, digestion and many other cellular functions.
In other parts of this series, we’ll cover how the liver and kidneys metabolize (use) and clear out (or detoxify or remove) opiates, how opiates increase or decrease neurotransmitter levels and other topics.

Chronic Pain Meds, Part 2: Opiate Side Effects

Opiates are codeine, oxycodone, hydrocodone and other drugs that relieve pain but have many potential side effects. Side effects come from their metabolites (breakdown products). Opiates are broken down (cleared, metabolized or “detoxified”) by the liver and kidneys. So who gets side effects and what are they? (covered more in Part 3). We have alternatives for pain management and/or strive to prevent or manage side effects.
Who gets drug side effects?
• Women, older patients and children.
• Patients with kidney problems. 1 in 9 Americans have silent kidney problems, which is easy to diagnose and then managed to prevent drug side effects.
• Patients with liver problems, which is difficult to diagnose. Certainly patients with “abnormal liver enzymes” on routine chemistries often have liver problems. Unfortunately, many people have problems with other liver drug clearance pathways that do not show on routine lab tests.
The liver breaks down many drugs, but especially opiates, via the CYP450 enzymes which are not tested on routine chemistries. 6-10% of Caucasian are deficient in one of these enzymes (CYP2D6 which is abbreviated as 2D6), but do not know it. CYP3A4 is the most abundant of these enzymes, but has wide variability on drug clearance (slow in some people, fast in others).
Codeine is converted by these enzymes into morphine, causing multiple drug interactions that may not be recognized. Low doses of codeine cause more nausea than higher dose, due to variable drug clearance.
Morphine (from codeine conversion) is converted into multiple sub-types. Sub-types are designed with an M (morphine), a number (1,2,3, etc.) and then G (for glucuronidation – a liver process that does not show on standard blood tests). M6G helps relieve pain. M3G causes more pain. Small amounts of morphine (from codeine) are turned into hydromorphone.
Hydrocodone (Vicodan, others) is converted by CYP2D6 into hydromorphone. Hydrocodone is one of the most abused drugs. In 2007, Florida pharmacies filled 3.8 million tablets per month (62 tabs per year for every citizen in Florida). Over 200 FDA approved products contain hydrocodone.
To review, codeine turns into morphine and hydromorphone. Hydrocodone converts into hydromorphone, which is 5 times more potent than morphine. Hydromorphone dissolves in water with less risk of drug accumulation if you have kidney failure.
Oxycodone (Percodan, Percocet, Oxycontin, others) is converted into oxymorphone and affects multiple brain receptors (opiate pain receptors, serotonin, dopamine, others). This is why we see the “perky Percocet” person who feels “up” and wants more Percocet to stay perky. This is also why we see insomnia, depression, memory and other brain problems with oxycodone. Oxycodone is extensively cleared by the liver, but by different enzymes than listed above.
Tramadol (Ultram) is a synthetic codeine and converted by 2D6 enzymes to become six times more potent. It can easily accumulate and cause side effects. Tramadol blocks serotonin and norepinephrine, potentially leading to more pain, sleep problems, anxiety, depression and other brain problems. The maximum dose of Tramadol is 400 mg per day and it should be avoided with older antidepressants. It can be helpful in neuropathic pain if used regularly in the extended release form. Drugs that block 2D6 enzymes block pain effects and slow down drug elimination leading to toxicity.

David Overton, PA-C works at Natural Medicines & Family Practice providing integrated conventional and alternative treatments under the supervision of Dr. Richard Faiola, MD, ABFM. 360-357-8054.