The Use of Long Acting Opioids and other Medications for Chronic Pain

Interview with Jeffrey Fudin, Pharm. D, R.Ph., DAAPM

Dr. Jeffrey Fudin is a Clinical Pharmacy Specialist at the Stratton VA Medical Center in Albany, NY. He is an Adjunct Associate Professor of Pharmacy Practice at the Albany College of Pharmacy, and an Instructor of Pharmacology and Psychopharmacology at SAGE Graduate School of Nursing. He is CEO of American Pharmaceutical Care Pain Consultants, a private Internet-based pain practice, www.paindr.com. He is on the Editorial Board and is the Pharmacy Clinician Expert for Rodale's Online Health. Dr. Fudin graduated from Albany College of Pharmacy (ACP) with his Bachelors Degree in 1981 and later, completed his Doctor of Pharmacy at ACP as well. He completed an American Cancer Society Sponsored Fellowship in Oncology / Hematology shortly after his undergraduate work. He is certified as a Diplomat to the American Academy of Pain Management, and a member of the American College of Clinical Pharmacy and other professional organizations. He was founder of the Pain Research Network Group of the American College of Clinical Pharmacy, and served as Chair for this group for 2 years. Dr. Fudin has been very active in pain management for several years and has been an invited speaker on this subject nationally and internationally. He has numerous publications in recognized professional journals, as well as a text book chapter. He has been very active in the "high tech" home care arena where he has advocated palliative medication alternatives for patients at home. He was instrumental in helping to establish the multi-disciplinary VA Pain Clinic at his institution, and has been key in developing policies in VA hospitals throughout the United States, with regard to pain as the fifth vital sign.

Pain.com: Lately, there has been a lot of press charging that pain is grossly under-treated. In your opinion, is this true, and if so, why do you believe it is a problem?

Dr. Fudin: Yes, unfortunately, I would have to agree with the press on this matter. Pain is in fact grossly under-treated in this country and most others. There have been numerous published local, national and international studies that point to this fact. By far, the two most common reasons are lack of education and fear of prescribing opioids. The far majority of professional schools of medicine, nursing, pharmacy, and others do not spend adequate time (if any) on training practitioners to treat acute and/or chronic pain. Most practitioners are left to learn this while practicing in the field by those who have not been adequately trained either.

Pain.com: Why do you think practitioners are fearful about prescribing opioids? Do you feel it is a legitimate fear?

Dr. Fudin: Many practitioners are afraid that they are being closely monitored by state and federal authorities such as the Bureau of Controlled Substances and the United States Drug Enforcement Agency. These agencies are set up to assure that narcotic medications are not being abused and/or diverted. If a practitioner has a legitimate reason to prescribe these medications, sees his/her patient on a regular basis, notes the patient's progress or lack of progress, and documents these activities, there is no reason to be fearful. If in fact the patient was involved in criminal activity, and a practitioner is acting in good faith and has documentation to that effect, punitive issues are unfounded. With regard to the toxicity of opioids, overall they are the safest of any chronically used pain medications, with the fewest side effects, if prescribed as single agents in long acting dosage forms.

Pain.com: Can you explain what you mean by "single agents, in long acting dosage forms?"

Dr. Fudin: Sure. The shorter acting medications are more appropriate for acute pain, and should be used on an as needed basis. Although there are single agent short acting opioid narcotics on the market, the most commonly prescribed short acting medications are those containing an opioid narcotic plus acetaminophen, aspirin, or ibuprofen. Unfortunately any of these three ingredients are far more toxic than the opioid they are usually combined with. Examples of these combination products include Tylenol with codeine (acetaminophen with codeine), Vicodin (hydrocodone with acetaminophen), Lortab (hydrocodone with acetaminophen), Percocet (oxycodone with acetaminophen), Percodan (oxycodone with aspirin), and many more. Don't misunderstand. I don't mean to say that these products aren't safe or effective. The point I want to make is that they are not medications that should be used each day around the clock, chronically. It is far more appropriate to use long acting medications in order to minimize several high blood concentrations throughout the day and to minimize the toxicity from chronic use of acetaminophen, aspirin, or ibuprofen.

Pain.com: What are some examples of long acting opioid narcotics?

Dr. Fudin: The most commonly used long acting opioids include MS Contin (extended release morphine), Oramorph-SR (extended release morphine), OxyContin (extended release oxycodone), and Duragesic transdermal Patches (continuous release transdermal fentanyl). Another older medication that is long acting by virtue of the way the body metabolizes it, is methadone. The other products in general are short-acting medications, but are pharmaceutically prepared for extended release. The disadvantage there is that you cannot crush the long acting oral dosage forms for the patient to swallow or to put down a gastric tube. If you did, the entire dose would be released at once, and that could be very dangerous. Methadone may be crushed and is easily dissolved. Because of the mechanism by which it is long acting, it will remain long- acting. Unfortunately, many practitioners are reluctant to prescribe methadone because of a fear that it will accumulate in the blood. In addition, many pharmacies will not stock it, for fear of being robbed or catering to patients that are "drug seekers". Still, if a practitioner is experienced with the use of methadone, it is a wonderful option.

Pain.com: Other than opioids, are there other pain medications that you find useful in treating cancer pain?

Dr. Fudin: Absolutely. The most important medications to use in a patient with metastatic bone pain are the NSAIDs (non-steroidal anti-inflammatories). In addition, cancer itself can cause tissue inflammation other than in bones, resulting in pain. Pain from bone cancer and pain from tissue inflammation are in large part due to a chemical known as prostoglandin. This chemical causes inflammation and pain, in some cases fever. The NSAIDs specifically inhibit the production of prostoglandins, thereby directly blocking inflammation and pain. These medications are as, or more important than the use of opioids alone for inflammatory pain. Very often, it is necessary to use a combination of NSAIDs and opioids. If a patient is allergic to NSAIDs, it is sometimes necessary to treat them with a steroid, such as dexamethasone or prednisone.

Pain.com: My understanding is that NSIADs are associated with peptic ulcer disease and can increase bleeding. Are cancer patients at a higher risk of these problems?

Dr. Fudin: Good question. Generally cancer patients are at a higher risk of gastric ulcer disease because of the chemotherapy they receive and because of the cancer itself. This puts them in a higher risk category for developing problems. Another issue is that many cytotoxic chemotherapy regimens used to treat cancer have a profound effect in lowering platelets, due to bone marrow toxicity. This of course makes a patient more prone to bleeding.

Pain.com: Are there any NSAIDs that are safer than others in this situation?

Dr. Fudin: Yes, there is a new class of NSAIDs known as the coxibs, or specific COX-2 inhibitors. COX-2 stands for cyclo-oxygenase-2. There are at least two iso-forms of COX. There is COX-1 and COX-2. COX-1 is associated with increased incidence of GI bleed, because it blocks the production of all prostoglandins, including those that are responsible for protecting the stomach. COX-1 also is responsible for the production of platelets, which in turn are involved in the activation of platelets for clotting. Therefore, the older more traditional NSAIDs like ibuprofen, naproxen, diclofenac, and many others, carry a higher risk of bleeding in the cancer patient. COX-2 blocks only those prostoglandins that cause pain, inflammation, and fever. The two COX-2 inhibitors currently available in the US include celecoxib (Celebrex) and rofecoxib (Vioxx). There are other important "pain" medications that I should include here as well. These are medications used to treat neuropathic pain. Neuropathic pain is generally associated with a feeling of burning and/or shooting pain. There are many types of neuropathic pain, but they are mostly treated the same way.

Pain.com: What are some examples of these medications, and how do they differ from NSAIDs and opioids?

Dr. Fudin: There are many classes of medications that are used to treat neuropathic pain. These generally include anti-depressants, anti-convulsants, anti-arrhythmics, and others. The most useful antidepresants include the TCAs (tricyclic antidepressants) and the SNRIs (serotonin norepinephrine reuptake inhibitors). The TCAs include medications such as amitriptyline, imipramine, desipramine and more. The SNRIs include venlafaxine (Effexor), nefazadone (Serzone), and mirtazapine (Remeron). There is literature supporting the fact that increasing norepinephrine in the synapse of nerves is the most important pharmacological mechanism by which antidepressants exhibit their effect in lessening neuropathic pain. Therefore, SSRIs (specific serotonin reuptake inhibitors) are generally not good choices in treating this type of pain, because they only increase serotonin. The TCAs I mentioned, and the SNRIs, all have an effect to increase both serotonin and norepinephrine, although deipramine is more specific for norepinephrine. The TCAs have a much higher toxicity profile than the SNRIs, including dry eyes, dry mouth, constipation, drowsiness, dizziness, cardiac conduction disturbances, and more. Anti-convulsants that have been most commonly used in the past include phenytoin (Dilantin) and carbamazepine (Tegretol). Phenytoin generally is no longer used for neuropathic pain, because it has a high toxicity profile, is difficult to titrate, and is involved with multiple drug interactions. Carbamazepine has been used with much success, but it too has a number of drug interactions and significant toxicity. It is still used with regularity and is relatively safe with close patient monitoring. Recently, a carbamazepine derivative with a better toxicity profile and a far lesser incidence of drug interactions came to market. This medication is known as oxcarbazine (Trileptal). Another excellent medication for neuropathy, which has relatively no drug interactions is gabapentin. It is dosed much higher than those doses usually used to treat convulsive disorders. The most commonly used anti-arrhythmic is mexiletine (Mexitil). It is usually not used first line, because is can actually cause arrhythmias. It will sometimes work where some of the other medications fail. Finally, some other medications used to treat neuropathy include capsaicin topical cream (a substnace P inhibitor), clonidine (a centrally acting alpha agonist), lidocaine transdermal patches (inhibiting ion influx into nerve cells), and methadone. Methadone, unlike the other opioids blocks special nerve receptors called NMDA (N-methyl D-aspartase). This blockade inhibits the nerve transmission of those nerves that cause neuropathic pain. Another medication not listed above that has good activity in both neuropathic and moderate to moderately-severe cancer pain is tramadol (Ultram). This is a unique medication, in that it has weak opioid activity and increases both norepinephrine and serotonin within the nerve synapse. The norepinephrine activity makes it useful in treating tumor pain where there is tissue destruction and nerve involvement.

Pain.com: Can any of the medications we discussed today be used in combination.

Dr. Fudin: Yes. To sum it all up, it is important for the medical practitioner to do a good pain assessment in order to qualify and quantify the nature of the patient's pain. Once this is done, many of the medications we discussed today can be used alone and/or in combination to obtain the maximal benefit for the patient, with the least toxicity. It is important of course to select medication combinations that will afford the patient the best benefit with the least toxicity, and to minimize drug interactions. It is therefore often important to consult a pharmacy clinician when devising combination regimens for pain management, especially if the patient is also additionally on multiple medications for other medical problems.

Pain.com: Thank you Dr. Fudin.