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New Treatments for Pain

Nine million patients suffer with cancer pain worldwide, 1.1 million in the United States. Overall incidence is 75% in cancer patients. When we think of a patient with pancreatic cancer we think that that’s going to be a much more likely malignancy to cause pain than say the lymphomas; although they all can. Those cancers growing within confined spaces within the marrow cavity.

We talk about pain syndromes. The most common pain syndromes are the somatic or visceral. The nociceptive pain syndromes. There are neuropathic pain syndromes. And when we talk about pain we talk about different types of pain, not only what is causing it but how much there is. And the term baseline pain refers to a pain that lasts for more than 12 hours. There are many descriptors of breakthrough pain. It could be incidental pain, it could be end-of-dose failure pain. They are transient pains that are over and above the baseline pain. The average patient with cancer will have four breakthrough pains a day. Anything more than four is unacceptable pain control.

The other adjuvant analgesics refer to a drug as a primary indication other than pain, but is analgesic in some painful conditions. This differs from a co-analgesic which is administered with a primary analgesic, to enhance pain relief and to allow decreasing opioid dose to decrease side effects. These are less reliable than the opioids in pain management.

So if a patient has depression, that’s fine if we get an antidepressant effect with them as well, but you can use them in patients that are not depressed and they can be effective. For the elderly, use a very low dose and use a higher dose for the young, and then you can increase this by the same dose that you started with every several days. Some people use a week, some people use every 3-4 days, until you start to get to the effective dose somewhere in the range. For these drugs you can look at levels in the blood and see where you are and how you are doing.

The anticonvulsants are predominantly effective for the episodic, the lancinating pain which peaks very rapidly in short duration. They probably act by dose suppression, neuro-discharges and decreased hyperexcitability and gabapentin is becoming the drug of choice.

The muscle relaxants; again, adjuvant analgesics. There is no evidence that these muscle relaxants actually relax skeletal muscle but they can be effective analgesics. You can gradually increase them to full dose. If you start them at full dose, many times you’ll have adverse effects that the patient will not tolerate well. I put this in for EMLA cream and it was a thick mixture.

Corticosteroids are extremely effective in dealing with patients with a pain in an emergency. This would be a very good drug to use right up front at a high dose, 20 mg three times a day or even higher for several days and then decrease it. They can have a significant analgesic effect and can last for several weeks.

Bone pain, a common metastatic disease, a periosteum has high density myelinated/unmyelinated afferent fibers and the radionuclides have been used predominantly for prostatic cancer. This will not cause complete pain relief in the great majority of patients. Only 10% of patients will have complete pain relief. Usually you can decrease the amount of analgesics they are taking when you give this, and you want an expected survival of usually at least three monthss.

As far as the opioids are concerned, narcotic refers to the legal term. When talking about pain management we are talking about the use of opioids. Opioids are derived from the Greek word for the juice of the poppy, opium, and it’s been used for euphoria as well as analgesia for greater than 5,000 years. Opiates refer to substances derived from this and there are many opioid preparations. So narcotic is a Greek word for stupor and it’s a legal term. When we are talking about treating patients we talk about opioids. We have endogenous opioids.

So these are the list of drugs that we have, the ones that we commonly use. You are going to have to know conversions. The starting dose of morphine is 0.1-0.15 mg parenterally per kilogram. That’s the starting dose of morphine that could be used, 0.1-0.15 mg per kg. Then these are typical conversion factors and you will have problems that are looking at those. You have to consider incomplete cross-tolerance when you go from one of these to another. What that refers to, especially at the higher doses - if you have someone on 10 mg of IV morphine and you want to switch to Levo-Dromoran for some reason - you would use 2 mg of IV Levo-Dromoran. But if someone is on 300 mg of IV morphine, if you went to 30 times.

If you have a patient who is on multiple analgesics and they are taking anxielitics, hypnotics, antidepressants, usually they have all those other comorbid problems because they don’t have adequate pain control. If you can relieve their pain you can get them off these other medications. So the question is, why aren’t they at a higher dose of opioids? If someone says, "So and so didn’t use … they took morphine and it didn’t work" why didn’t it work? Was it uncontrollable side effects? That would be the only answer that would be acceptable, really.

So the order should be written around the clock, hold for somnolence, a respiratory rate of less than 10, sometimes 12. Not 14. And that means difficulty arousing, not normal wake/sleep behavior. These are safe drugs to use for the elderly patient with COPD, renal problems, hepatic impairment, but they have to be used slower. Start a lower starting dose.

Supplemental dose for breakthrough pain; there are many formulas that have been used. In general, the one that most people would use is to take a 24 hour dose of opioid that someone has good pain control on, and give them 10-15% of that every 2-3 hours for breakthrough pain; 10-15% of 24 hour dose of the same drug. If you are on long-acting opioid, short-acting opioid.

Talk about some of the specific drugs. Propoxyphene; this is a synthetic analgesic, structurally related to methadone. There may be some NMDA inhibition with this drug. It is at best, at best, a weak opioid. There’s a metabolite, norpropoxafine, which has a very prolonged half-life and can cause significant CNS toxicity. So this should be a very minor player, used very infrequently for the patients that we are dealing with that need opioids. Codeine; low affinity for the mu-receptor, lower than all the other opioids. Some patients will lack the demethylating enzyme and codeine is demethylated to morphine. So 5-15% of patients won’t be able to activate this drug to morphine, so you may not be able to use this drug. Meperidine.

Hydromorphone; semisynthetic opioid. This is Dilaudid for those of you not familiar with that. Thirty-four percent bioavailability. It’s the drug of choice for chronic subcutaneous use because it can be formulated in very very concentrated amounts.

Methadone; extremely inexpensive drug, and it’s a very effective opioid. The group in Canada, Edmonton, has published a lot on methadone. The problem with methadone is that some of the metabolites have a very prolonged half life, some up to 60 hours. So it’s a drug that should be used very cautiously and really by those who are used to using it.

Oral fentanyl; trans-mucosal. This has just been released. This is … the drug is Actiq. It’s a rapid in and rapid out. It can have a peak affect relatively early, faster than any of the other opioids. The interesting thing about this drug; if you have a patient on transdermal fentanyl and

A couple of drugs, I’d like to point out some things about some of the nuances of some of these other drugs; MS Contin, the prolonged release morphine, the maximum effect in three-and-half hours, whereas immediate release morphine maximum effect in about 1.3 hours.

Rectal morphine equi-analgesic to oral. Same doses that you would use orally and it’s just as effective. In fact the area under curve with the absorption of this drug is a little bit higher than with oral morphine.

OxyContin versus oxycodone; immediate release oxycodone basically is the same time to maximum effect as the prolonged OxyContin. Again, this should be used every 12 hours. A small group of patients will need it every 8.

Transdermal fentanyl; this is the derma-gesic 25, 50, 75, 100 microgram patches. When you put a patch on you can’t detect this in the blood for about two hours afterwards. You don’t have your therapeutic effect until you are about 14-18 hours afterwards and your peak effect is about a day afterwards. A good Board question would be, "If you have a patient who is on long-acting opioids orally and you want to switch them over to transdermal fentanyl.

Subcutaneous administration is used predominantly at the very end stage of life and a great majority of patients will need multiple routes of administration, especially late in their disease. Intraspinal opioids; introduction of minute quantities of opioids in close proximity to receptors and you can decrease your systemic opioid toxicities, oftentimes by giving intraspinal.