Background: In 1995 the Robert Woods Johnson Foundation reported about their "SUPPORT" study in JAMA. They found that 42% of patients with cancer had received inadequate pain relief. The causes were attributable to both family fears and physician fears about addiction as well as ignorance about best methods of giving pain relief. After a year of attempts to alter the situation they repeated the study and found virtually no change. The AMA and many other medical organizations are now making efforts to change the philosophy and knowledge about relief of pain in terminally ill patients. The key to hospice and palliative medicine seems to be the realization that the goal of treatment is not to cure or make futile attempts to restore the patient to their productive life, but to relieve the patient of symptoms near the end of their life. Communicating these goals to both family and patient are essential. The actions of Dr. Kevorkian in Michigan and the Oregon law legalizing physician assisted suicide are stimulants for much of the effort.

The physiology and biochemistry of pain receptors and transmitters are in full research mode. Peptides, neuronal plasticity, and excitatory amino acids (NMDA) are not of much interest to practicing physicians but research is exploding; and new drugs and new approaches to treatment are coming down the pike quickly. For example very small doses of Versed combined with hypnotherapy seem to allow less apprehension and better receptiveness from the patient and therefore hypnotherapy is much more effective. Pharmacological methods remain the cornerstone of management.

Prevent persistent pain and relieve breakthrough pain. Patients can be switched to "by the clock" dosing or long acting dosing after a few PRN doses to establish the approximate 24 hour total dosage. Supplemental breakthrough PRN doses should remain available.

Pancreatic cancer pain can be greatly reduced by intra-operative splanchnicectomy or celiac plexus obliteration. Not only is later pain much less and mood improved but survival time is actually longer.

The shooting, lightening-like, stabbing pain aggravated by movement is usually of neuropathic origin; it is not well relieved with narcotics. Several approaches should be available and more than one may be needed.

Anticonvulsants are widely used and sometimes helpful. These include Dilantin, Tegretol, and Valproic acid. Gabapentin (Neurontin) has become the anticonvulsant of first choice for neuropathic pain. It is of interest that this is not a GABA agonist as originally thought. It’s mechanism of action is not known with certainty.

Baclofen is a true GABA agonist and is sometimes useful.

Antidepressants, both tricyclic and selective serotonin reuptake inhibitors (SSRIs), are also widely used. If they are going to be effective, they will do so much faster than when treating depression.

Local anesthetic agents used both locally and systemically are useful. These include lidocaine, bipivucaine, mexilitine, and flecanide.

A new calcium channel blocker, Neuronex, is derived from a snail toxin. It is due to be released soon with its primary indication being that of neuropathic pain.

NMDA antagonists such as Ketamine are useful but can have adverse psychological effects. In most hospice literature, that is used mostly in terminal states. Memantine, now used in Parkinson’s disease has been used with success.

As you can tell by the myriad of available drugs for use with this difficult condition, patients with neuropathic pain are prone to polypharmacy which can bring on a whole new set of problems. Good clinical judgment is especially needed for this challenge.

Step 1 Drugs: NSAID’s are all similar, are best used for bone pain, and usually are combined with your narcotic of choice for best results.

Step 2 Drugs: Codeine (Tylenol #2,3,4) and it’s synthetic derivatives are good second line narcotics. These include Dihydrocodeine (Synalgos DC), and Hydrocodone (Lortab, Vicodin).

Oxycodone (Tylox, Percodan, Roxicodone) has gained much credibility in progressive pain. It can be tritrated upward as far as needed and does not have the "tic" associated with morphine. It may soon rival morphine as the new "gold standard." Oxycontin is a controlled release oxycodone and is usually considered a step 3 drug.

Step 3 Drugs: Morphine remains the gold standard of narcotic therapy for pain. It comes in various forms with various duration of action. (MSIR, MS Contin, Oramorph ST, Roxanol). A fairly new one, Kadian, has a duration of action of 24 hours which is probably too long to be of most practical value. It has a redeeming quality in that it comes in pellets in a capsule which can be opened and sprinkled on puddings, sauce, etc. for those that cannot swallow tablets. The one disadvantage of all natural narcotics is the sometimes occurring tick or slow myoclonic jerk which may occur in higher doses.

Hydromorphone (Dilaudid) is a semi-synthetic form, usually free of tics, but has no long acting oral form. It has only the immediate release or parenteral short acting forms. When needed in high doses, it can be made in a very concentrated form for use in a subcutanteous port and still keep the patient at home.

Fentanyl (Duragesic) is lipid soluble and can therefore be used topically when the patient cannot swallow. The biggest drawback is its' extremely long duration of action of 3 days which makes changing doses more difficult. A new oral form, trade name, "Actiq," will soon be released. It is ultra short acting (onset in 5 minutes and gone in 30 minutes) and will be ideal for breakthrough pain.

Pearl #4: Newer drugs:

Tramadol (Ultram). It is more than an NSAID but less useful than codeine because it cannot be titrated upward as pain increases. The customary dose of 50 mg. is approximately equivalent to codeine 60 mg.

Samarium 153 (Quadrament). New and more effective than strontium 89 for bone pain mets. It has quicker onset and better bone marrow recovery according to early reports.

Clonidine, an alpha-2 agonist, has been found useful. A new preservative-free solution (Duraclon) for use in epidural administration combined with a narcotic has shown great promise for resistant cases. The response for somatic pain is 45% vs. 29% with morphine alone. For neuropathic pain the response rate is 56% vs. 5% for morphine alone. In some centers it is now being used off-label intrathecally for neuropathic pain with excellent results.

Gray Pearl: Nebulized morphine.

This is a recent fad being used for endstage COPD as well as chest pain. Most current studies are showing it to be no more effective than plain oral morphine.

Black Pearls: Drugs not recommended:

Darvon and Darvocet-N are popular for mild pain but have no place in pain for malignancy. They cannot be titrated upward. Acetominophen becomes toxic when doses are increased.

Stadol, Nubaine, Talwin, and Buprenex are used extensively to prevent addiction. But they have no place in progressive cancer pain. They cannot be titrated upwards. And there is the real danger that when combined inadvertently with a potent narcotic, they will reverse the narcotic with catastrophic effects.

Demerol is popular as a short term post-operative pain narcotic. However with progressive chronic pain a toxic metabolite accumulates which can cause seizures.

Methadone’s duration of action is too long to allow easy changing of doses. There are too many other intermediate acting narcotics which are more practical to use.

Ninety-five to ninety-eight percent of cancer pain can be controlled with the drugs mentioned above. The other two to five percent may require heroic treatment such as radiation or epidural or intrathecal injections which is beyond the scope of this paper. Rarely additional chemotherapy may be used, but more often is used at the request of a family in denial and demanding attempted curative therapy even when the side effects outweigh any possible benefits. This last situation is especially common in parents who cannot stand the thought of losing a child.

Pearl #5: Treatment should be as simple and non-invasive as possible.

Pearl #6: Addiction to opiates should not preclude treatment; but some rules should be laid down. One physician, one pharmacy, limited amounts of medication per prescription, frequent physician visits, renewals contingent on visits, and no change in medication without permission are the basis of care in which the benefits will outweigh harm. Drug abuse with a caregiver requires the same rules. Where there is no addiction before treatment for malignant pain, the liklihood of developing addiction is quite rare.

Pearl #7: When switching from one drug to another, or from one route to another, refer to one of the numerous pharmacological tables for equivalence.

To convert morphine to or from transdermal fentanyl:

References:

American Pain Society. Principles of analgesic use in treatment of cancer pain. 3^rd edition. Skokie. 1992
Cherny NG, Portenoy RK. The management of cancer pain. Ca:Cancer J Clin 1994:44:262-303
Doyle D, Hanks GWC, MacDonnald N, Eds. Oxford textbook of palliative medicine; 1993
Faymonville MD; Manbourg PH.7 Psychological approaches during conscious sedation. Pain 1997 Dec: 73(3):361-7
Jacox AK, Carr DB, Payne R. Management of cancer pain. Clinical practice guideline no 9. Rockville, MD (AHCPR publication no. 94-0592)
Levy MH: Pharmacologic treatment of cancer pain. N engl J Med 1996;335:112-32
Levy MH: Pharmacologic treatment of cancer pain. Semin Oncol 1994; 21:718-739
Levy MH: Integration of pain management into comprehensive cancer care. Cancer 1989;63:2328-35
Patt RB, ed. Cancer Pain. Philadelphia, J.B. Lippincott co; 1993
Procedings, Advanced Pain Management Symposium, American Academy of Hospice and Palliative Medicine; 1998
Study to Understand Prognoses and Preferences for Outcomes, and Risks of Treatment (SUPPORT). J Amer Med Assoc 274:1591-1598, 1995
Twycross R. Pain relief in advanced cancer. London, Churchill Livingstone; 1994.

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