P&T News: March 1998
Barbara L. Kaltenbach, Pharm.D., and Amy J. Becker,
Pharm.D.
Peer Review Status: Internally Peer Reviewed by
Robert Dreicer, M.D., Associate Professor, Division of
Hematology/Oncology, Department of Internal Medicine
Overall, morphine remains the most commonly used opioid due to its relatively low cost, the availability of numerous dosage forms, and the amount of literature available regarding its use.3 Meperidine and propoxyphene are not recommended for chronic use due to the accumulation of potentially toxic metabolites.2, 3 In addition, although not as toxic as meperidine and propoxyphene, methadone is not recommended for initial therapy due to the potential for drug accumulation resulting in extreme sedation.6 When initiating drug therapy, it is helpful to use only one analgesic medication at a time; this will avoid the problems associated with polypharmacy and will provide the most effective titration to reach the best dose as well as limit potential adverse effects.1, 3 Table I shows the available dosage forms for opioid products stocked at UIHC; Table 2 provides the recommended starting doses for initiating opioid therapy in an opioid-naive patient.
| Table 1: Opioid Products Available at UIHC | |||||
| Product | Enteral | Parenteral# | Transdermal | ||
|
Immediate-release, oral (IR) |
Sustained-release, oral (SR) |
Rectal |
|||
|
Morphine |
10, 15 mg tablets* |
15, 30, 100, 200 mg tablets |
-+ |
1, 2, 4, 8, 10, 15, 25, or 50 mg/mL |
- |
|
Hydromorphone |
2, 4 mg tablets |
- |
3 mg |
1 mg/mL, 2 mg/mL |
- |
|
Codeine |
15, 30, 60 mg tablets |
- |
- |
15 mg/mL, 30 mg/mL |
- |
|
Oxycodone |
5 mg capsules |
10, 20, 40 mg tablets |
- |
- |
- |
|
Fentanyl |
- |
- |
- |
0.05 mg/mL |
25, 50, 75, or 100 mcg/hr patch |
APAP = acetaminophen
| Table 2: Recommended Starting Doses of Opioids1, 6 | ||
|
Product |
Dose for Mild to Moderate Pain# |
Dose for Moderate to Severe Pain# |
|
Morphine |
not recommended |
15 to 30 mg |
|
Hydromorphone |
not recommended |
4 to 8 mg |
|
Codeine |
30 to 60 mg |
not recommended |
|
Oxycodone+ |
5 mg |
15 to 30 mg |
|
Hydrocodone~ |
5 to 10 mg |
not recommended |
|
Fentanyl |
Patch not recommended for use in opioid-naive patients; titrate first with other agents and then use conversion table to convert to patch. |
|
Initiating Therapy
Overall, the oral route of administration should be used whenever
possible.5, 6 This route offers the greatest convenience as well as
flexibility in choosing which product to use. An immediate-release
product should be chosen from the table of available products. For
immediate-release products, the peak effect occurs in approximately
two hours (see Table 3) and patients may be instructed to take
additional medication if pain relief does not occur by this point (as
long as side effects are manageable).6
| Table 3: Estimated Product Pharmacokinetics 1, 3, 6 | |||
|
Product |
Onset of Action |
Peak Effect |
Duration of Action |
|
Immediate-release, oral (morphine, hydromorphone, codeine, oxycodone, hydrocodone) |
0.5 hr |
1.5 to 2 hr# |
4 hr |
|
Sustained-release, oral (MS Contin[R], OxyContin[R]) |
1 hr |
2 to 3 hr |
12 hr |
|
Subcutaneous (morphine or hydromorphone) |
10 to 15 min |
- |
3 to 4 hr |
|
Intravenous (morphine or hydromorphone) |
5 min |
15 to 30 min |
1 to 2 hr |
|
Intravenous (fentanyl) |
almost immediate |
1 to 5 min |
0.5 to 1 hr |
|
Transdermal (fentanyl) |
12 hr |
24 to 48 hr |
72 hr |
Once a patient's pain has started to stabilize and an effective daily dose can be estimated, immediate- release preparations can be converted to sustained-release preparations. All patients stabilized on sustained-release products should still have an immediate-release form available for breakthrough pain.3, 6 Ideally, all chronic pain patients should have one sustained-release product and one immediate-release product of the same medication (e.g., sustained-release morphine and immediate- release morphine), though this may not always be possible (e.g., hydromorphone may be effective as an immediate-release preparation, but is not available in sustained-release form). In addition, the total daily dose of the immediate-release product available should be equal to the total dad) dose of sustained-release product the patient is using.3 For instance, if a patient is using 30 mg of MS Contin every 12 hours, the total daily dose is 60 mg and thus the patient should have available 10 mg of immediate-release morphine to take every four hours for breakthrough pain (total of 60 mg of immediate-release product available).
While the oral route is optimal for a patient stabilized on therapy, it is obviously a poor choice for someone with fluctuating degrees of pain where the dose may need to be changed rapidly. For these patients, the parenteral route is preferred. The intravenous route will provide rapid pain relief; onset of analgesia typically occurs almost immediately for fentanyl and within 15 to 30 minutes for morphine. Subcutaneous administration will also provide rapid pain relief, though not quite as rapid as with intravenous administration; time to onset of analgesia has been reported to occur within 10 to 15 minutes,3 but may vary from patient to patient depending on a number of patient-specific factors.7, 8 Intramuscular administration is not recommended due to discomfort for the patient as well as variability in absorption.5, 6 Epidural and intrathecal administration are other, more complicated pain mitigation options which will not be discussed here.
Three routes of administration used less commonly are the sublingual, the rectal and the transdermal routes, all of which can be used when the oral route is not feasible and should be used, if possible, prior to the more invasive, parenteral routes.5 The sublingual route can be used if the patient is having difficulty swallowing. Both morphine solution and soluble tablets of morphine can be given sublingually. The rectal route can be unpleasant for many patients and is most appropriate when patients are temporarily unable to take oral therapy. If rectal dosage forms are unavailable, MS Contin[R] can be administered rectally.1 Fentanyl, as the Duragesic[R] patch, which is applied every 72 hours, is the only product currently available as a transdermal system. The onset of pain relief begins approximately 12 to 14 hours after the patch is applied and, as a result of a subcutaneous depot that is formed, the medication will continue to be absorbed systemically for up to 24 hours after patch removal.1 Due to these unique pharmacokinetic properties, Duragesic should be reserved for patients whose pain is stable; it should not be used as initial therapy. When starting Duragesic[R], it is especially important to ensure that the patient has adequate analgesics available to cover the 12 to 14 hours that it typically takes for pain relief to occur with this dosage form.
Titrating Therapy
There is a great degree of variation in terms of the opioid lid
dose that will provide the greatest efficacy for each patient.6 Do
not be afraid to continue to increase a patient's medication when the
dose is no longer controlling the pain; maximum dosage levels are
different for each patient and doses need to be individually titrated
upward to response.1, 5 Tolerance is common in all patients
taking opioids chronically and patients may eventually require higher
doses of opioid medication due to tolerance or due to progression of
illness. It is important to recognize that this increasing need and
physical dependence does not equate with psychological dependence
(i.e., addiction). Health care professionals are often hesitant to
provide patients who have increasing pain control needs with higher
doses of narcotics for fear that these patients will become addicted,
and family members often concur. However, long-term experience in
cancer pain management suggests that addiction in patients using
opioids for cancer pain is extraordinarily uncommon.
If a patient's pain is increasing only at certain times of the day, the patient may be instructed to take additional immediate-release medication around that time of the day. However, if overall baseline pain has increased, adjustment of the dose of the sustained-release product is warranted. Levy3 recommends focusing on increasing the dose in these cases rather than shortening the interval. Only in rare cases will a patient require an interval change from every twelve hours to every eight hours for an oral sustained-release product.
Current practice guidelines, developed by the American Society of Anesthesiologists,5 recommend a minimum increase of 25 to 50% of the previous day's dose. As an example, if a patient was using 15 mg of immediate-release morphine every four hours (90 mg total for 24 hours) and still experiencing pain, an appropriate increase would be approximately 20 to 50 mg of additional morphine over the next 24-hour period. Levy recommends an increase of 50 to 100% if the patient is still experiencing pain rated at five or greater on a scale of one to ten 24 hours after a dose increase.
If pain relief is still not adequate despite optimal dosage increases, or if a patient starts to experience unmanageable side effects, switching to another opioid is a viable option as patients will have decreased tolerance to other opioids. According to practice guidelines, one opioid should be substituted for another at 50 to 75% of the equianalgesic dose.5 Table 4, which lists equivalent doses of opioids, can be used to obtain the equianalgesic dose of an opioid when one is substituted for another, as well as to convert from one route of administration to another. An easy way to make the conversion, especially if the patient is taking more than one product, is as follows: For each type of opioid product the patient is using, determine the cumulative dose in mg over a 24-hour period and convert to oral morphine. Next, convert from oral morphine to the new medication chosen for the patient. Lastly, decrease this new dose by about 25 to 50%. These steps will provide an estimate of the best starting dose of the new medication for the patient.
| Table 4: Opiod Conversion Table3, 5, 6 | |||
|
Medication |
Parenteral Dose |
Enteral Dose |
Parenteral to Enteral Ratio |
|
Morphine |
10 mg |
30 mg |
1:3 |
|
Hydromorphone |
1.5 mg |
7.5 mg |
1:5 |
|
Codeine |
130 mg |
200 mg |
1:1.5 |
|
Oxycodone |
- |
15 to 30 mg# |
NA |
|
Hydrocodone |
- |
30 mg |
NA |
|
Fentanyl* |
0.1 mg |
- |
NA |
If it becomes necessary to decrease or discontinue a patient's opioid therapy, a downward titration should be used so as not to precipitate withdrawal symptoms (chills, diaphoresis, abdominal cramping, vomiting). The American Pain Society recommends decreasing the dose initially by 50% for two days, then by 25% every two days until the equivalent of a 30 mg daily oral morphine dose is reached. Use this dose for two days and then discontinue therapy.6
Adverse Effects
Unfortunately, relief of pain through the use of opioid therapy is
not without adverse effects. Some common adverse effects associated
with opioids include constipation, nausea, sedation and pruritus. Of
these, constipation is probably the most common and, though
patients will become tolerant to many of the adverse effects of
opioid therapy, most will not become tolerant to constipation.1
Preventative measures, such as dietary fiber and/or laxatives, are
recommended for any patient taking opioid analgesics.2, 3 One example
of a regimen developed by the American Pain Society includes 100 to
300 mg of docusate sodium per day along with two to six tablets of
senna twice daily.6 Levy, however, suggests that stool softeners may
not be effective. He recommends initiating therapy with senna,
titrated up to four tablets three times daily, if needed, followed by
bisacodyl, two to three tablets up to three times daily if no bowel
movement has occurred in a 48-hour period.1 The extent of laxative
therapy required will vary from patient to patient.
Though nausea generally does not last long into therapy, initial bouts of nausea can be treated with medications such as metoclopramide or prochlorperazine.2, 5 Sedation, as well, is typically only a problem at the onset of therapy; tolerance to the sedative effects of opioids will occur as therapy continues. Combining opioid medications with nonsedating analgesics (e.g., acetaminophen) may lessen sedation.3 Pruritus, due to histamine release, may occur with initial therapy and may be treated with diphenhydramine. Pruritus does not indicate an allergy to opioid therapy.1 Gastrointestinal upset or pruritus is often reported by patients as opioid allergies; however, true allergies to opioid therapy are rare and typically manifest as an anaphylactic reaction. If a patient does have a true morphine allergy, methadone and fentanyl are generally safe alternative agents to use. Their chemical structures are distinct enough from morphine that a cross-reaction is not likely to occur.
In a patient chronically treated with opioids, especially if appropriate titration has occurred, respiratory depression is not a clinically relevant problem. In opioid naive patients, monitoring the patient for several hours beyond the expected peak effect of the medication (see Table 3 for estimated peaks) for signs of respiratory depression is warranted.6 If it becomes necessary to reverse respiratory depression in a patient who has been taking opioids for more than one week, the American Pain Society recommends a 0.4 mg dose of naloxone diluted in 10 mL of 0.9% sodium chloride to be given IV push, as 0.5 mL every two minutes as needed.6 Once respiratory status is stable, taper down or stop naloxone one to avoid reversing analgesia and precipitating a pain crisis. If a patient is on an intravenous opioid infusion, stopping or slowing the infusion may also be adequate to improve respiration.
Adjuvant Agents
Various medications can be used as coanalgesics to opioid treatment
and may be particularly beneficial as add-on therapy in certain types
of pain.1, 5, 6 Table 5 lists some adjuvant agents that are useful in
certain patient populations. Nonsteroidal anti-inflammatory
medications, corticosteroids, anticonvulsants, and antidepressants
are the most common classes used. The use of coanalgesics, however,
is not without potential problems and/or adverse events, as noted in
Table 5.
| Table 5: Adjuvant Pain Medications1, 5, 6 | ||
|
Adjuvant Medication |
Type of Pain |
Comments |
|
Nonsteroidal anti-inflammatory drugs |
Bone pain; soft tissue infiltration |
Avoid use if patient is thrombocytopenic, has an ulcer or gastrointestinal bleed, or is experiencing renal insufficiency. |
|
Tricyclic antidepressants |
Neuropathic pain; pain with depression or insomnia |
Greatest experience is with amitriptyline; however, it has strong anticholinergic effects, such as constipation and dry mouth. |
|
Benzodiazepines |
Pain associated with anxiety or muscle spasm |
Due to a respiratory depressive effect, a benzodiazepine may limit the amount of opioid that can be given; may cause mental status changes. |
|
Corticosteroids |
Nerve or spinal cord compression; soft tissue infiltration |
Rapid withdrawal of steroid may exacerbate pain. |
|
Anticonvulsants |
Nerve injury or neuralgia |
Carbamazepine and clonazepam are the drugs of choice - use caution with carbamazepine in patients who are expected to become neutropenic; gabapentin and baclofen are other options. |
Conclusion
There are a number of pharmacologic options for the management of
chronic pain in patients with cancer. The appropriate choice and
dosing of these agents, along with the management of adverse effects,
can lead to adequate pain control in most of these patients. It is
important to keep in mind that each patient is different in terms of
pain control needs and will require individual titration and
management. A patient who expresses escalating pain should have
appropriate adjustments made in opioid doses; concern of addiction
should not become an obstacle in receiving adequate pain control. It
is stressful enough for patients and family members to cope with a
cancerous condition. Inadequate pain relief does not have to be an
added stress. Quality patient care in the area of pain management can
lead to an increased quality of life.
References
Drugs Added to Stock
CABERGOLINE Tablet: 0.5 mg Cabergoline (Dostinex[R] - Pharmacia & Upjohn) tablets are indicated for the treatment of hyperprolactinemic disorder of either idiopathic or pituitary adenoma etiology.
DANAPAROID Injection: 750 anti-Xa units per 0.6 ml Danaparoid (Orgaran[R] - Organon) injection is a low molecular weight heparinoid indicated for the prevention of deep vein thrombosis. NOTE: The prescribing of danaparoid is restricted to prescribing by attending staff physicians from Adult and Pediatric Hematology/Oncology.
DIHYDROERGOTAMINE Nasal Spray: 4 mg per ml Dihydroergotamine (Migranal[R] - Novartis) nasal spray is indicated for the acute treatment of migraines with and without aura.
DOXORUBICIN, LIPOSOME Injection: 2 mg per ml, 10 ml vial Doxorubicin liposome (Doxil[R] - Sequus) injection is an antineoplastic agent. NOTE: The prescribing of doxorubicin liposome injection is restricted to the following criteria: ovarian cancer refractory to standard treatment regimens; approved research protocol; and Kaposi's sarcoma.
HUMAN ALBUMIN MICROSPHERES Injection: 3 ml Human albumin microspheres (Optison[R] - Mallinckrodt) in octafluoropropane injection is used for contrast enhancement during cardiac ultrasound imaging procedures.
IMIQUIMOD Cream: 5% Imiquimod (Aldara[R]. - 3M) is an immune response modifier indicated for the treatment of external genital and perianal warts (condyloma acuminate).
MANGAFODIPIR Injection: 37.9 mg per ml Mangafodipir (Teslascan[R] - Nycomed) is an intravenous contrast agent for MRI used to enhance visualization of lesions of the liver.
MONTELUKAST Tablet: 10 mg Chewable Tablet: 5 mg Montelukast (Singulair[R] - Merck) is a selective leukotriene receptor antagonist indicated for prophylaxis and chronic treatment of asthma in adults and pediatric patients at least 6 years of age.
OXYCHLOROSENE Powder: 2 g Oxychlorosene (Clorpactin WCS-90~ - Guardian) is a topical antimicrobial agent used for treatment of localized infection and as an irrigating agent.
PROGESTERONE Vaginal Gel: 8% Progesterone (Crinone[R] - Wyeth-Ayerst) 8% vaginal gel is indicated for progesterone supplement or replacement as part of an assisted reproductive technology treatment in infertile women.
RALOXIFENE Tablet: 60 mg Raloxifene (Evista[R] - Lilly) is a selective estrogen receptor modulator indicated for the prevention of osteoporosis in post-menopausal women.
RITUXIMAB Injection: 10 mg per ml Rituximab (Rituxan[R] - Genentech) injection is an antineoplastic agent indicated for the treatment of relapsed or refractory low-grade or follicular CD20 positive B cell, non-Hodgkin's lymphoma.
NOTE: The prescribing of rituximab is restricted to Adult and Pediatric Hematology/Oncology.
SUMATRIPTAN Nasal Spray: 20 mg per 0.1 ml Sumatriptan (Imitrex - Glaxo Wellcome) nasal spray is indicated for the acute treatment of migraines with or without aura.
TOBRAMYCIN Inhalation Solution. 300 mg per 5 ml ampul Tobramycin (TOBI - PathoGenesis) inhalation solution is indicated for the management of cystic fibrosis in patients with Pseudomonas aeruginosa.
NOTE: The prescribing of tobramycin inhalation solution is restricted to prescribing by the Pediatric Pulmonary/Allergy Division for cystic fibrosis patients.
TOLCAPONE Tablet: 100 ma, 200 mg Tolcapone (Tasmar[R] - Roche) is an inhibition of catechol-o-methyl transferase (COMT) indicated as adjunct therapy to levodopa and carbidopa for the treatment of Parkinson's disease.
VENLAFAXINE Sustained-Release Capsule: 37.5 ma, 75 ma, 150 mg Venlafaxine sustained-release capsules (Effexor[R]XR - Wyeth- Ayerst) are indicated for once-daily dosing for the treatment of depression.
Additional Actions
BUPROPRION SUSTAINED-RELEASE TABLET (ZYBAN[R]) This product was added to stock as an aid for smoking cessation. NOTE: The Zyban[R] brand of bupropion sustained-release must be specified in order to obtain the manufacturer's auxiliary patient education materials for smoking cessation.
CALCIUM 500 mg WITH VITAMIN D 125 IU TABLETS This combination product has been added to stock.
ESTROGENS, CONJUGATED WITH MEDROXYPROGESTERONE (PREMPRO[R] 0.625 ma/ 5 ma) This additional strength was added to stock. NOTE: In order to ensure the appropriate strength is dispensed, the prescriber must specify PremPro 0.625 mg/S ma; PremPro[R] 0.625 mg/2.5 mg is also available.
GANCICLOVIR 500 mg CAPSULES The 500 mg strength has been added to stock.
PRENATAL VITAMINS (ENFAMIL NATALINS[R] RX) This product replaces Natalins[R] Rx. Per Pharmacy and Therapeutics Subcommittee authorization for orders written for "prenatal vitamins with folic acid" or "prenatal vitamins with I mg folic acid" this product or similar product, which contains 0.5 mg of folic acid, will be dispensed at a dose of one tablet per day for pregnant patients.
TETRACAINE 20 mg INJECTION (PONTOCAINE[R]) This preservative-free preparation was added to stock.
Drugs Deleted from Stock
ACI-JEL VAGINAL OINTMENT Discontinued due to low use. Boric acid vaginal capsules are available.
AMINO ACIDS 5.4% INJECTION (NEPHRAMINE[R]) Discontinued due to low use. Amino acids 15% injection (Novamine[R]) is available.
ASPIRIN 120 mg SUPPOSITORIES Discontinued by all manufacturers. Aspirin 300 mg suppositories are available.
CALCIUM GLUCONATE TABLETS (9% CALCIUM) Discontinued due to low use. Calcium carbonate tablets (40% calcium) and calcium citrate tablets (21% calcium) are available.
CARBINOXAMINE WITH PSEUDOEPHEDRINE TABLETS (RONDEC[R]) Discontinued due to low use. Dimetapp[R] Extentabs, Drixoral[R] tablets, Actifed[R] tablets, and Claritin-DX 24-Hour tablets are available.
COLFOSCERIL PALMITATE PULMONARY SURFACTANT (EXOSURF[R]) Discontinued due to low use. Beractant pulmonary surfactant (Survanta[R]) is available.
DIAZEPAM EMULSIFIED 5 mg/ml INJECTION (DIZAC[R]) Discontinued due to low use. Diazepam 5 mg/ml injection (Valium[R]) is available.
DIGOXIN SOLUTION IN CAPSULES (LANOXICAPS[R]) Discontinued due to low use. Digoxin tablets (Lanoxin[R].) are available.
EPINEPHRINE ORAL INHALER (AsthmaHaler[R] MIST) Discontinued due to low use. Isoproterenol oral inhaler, Metaproterenol oral inhaler, and Terbutaline oral inhaler are available.
ERGOTAMINE AND CAFFEINE SUPPOSITORIES (CAFERGOT[R]) Discontinued due to low use. Ergotamine and caffeine tablets (Cafergot[R]) are available.
ETHINYL ESTRADIOL 0.05 mg TABLETS (ESTINYL[R]) Discontinued due to low use. Ethinyl estradiol 0.02 mg tablets are available.
HOMATROPINE 2% OPHTHALMIC SOLUTION Discontinued due to low use. Atropine 0.5% and 170 ophthalmic solution are available.
INSULIN, LENTE PORK U-100 (ILETIN II[R]) Discontinued due to low use. Insulin, lente human U-100 (Humulin.) is available.
INSULIN, REGULAR-NPH 50-50 MIXTURE, HUMAN U-100 Discontinued due to low use. Individual components are available.
ISOSORBIDE DINITRATE SUBLINGUAL TABLETS Discontinued due to low use. Isosorbide dinitrate oral tablets and nitroglycerin sublingual tablets are available.
LEVODOPA 250 mg TABLETS Discontinued due to low use. Carbidopa-levodopa tablets (Sinemet.) are available.
MINOXIDIL 2% TOPICAL SOLUTION (ROGAINE[R]) Discontinued due to low use.
NATALINS[R] Rx PRENATAL VITAMINS Discontinued by the manufacturer. Replaced with Enfamil Natalins[R] Rx.
ORAL REHYDRATION SALTS (W.H.O. SOLUTION) Discontinued due to low use.
PAPAVERINE CAPSULES Discontinued due to low use. Papaverine injection is available.
PHENYLEPHRINE 0.12% OPHTHALMIC SOLUTION (PREFRIN., ISOPTOFRIN[R]) Discontinued due to low use. Phenylephrine 2.5% ophthalmic solution (Neo-Synephrine[R], Mydfrin[R]) is available.
SENNA CONCENTRATE GRANULES (SENOKOT[R]) Discontinued due to low use. Senokot(3) tablets and Senokot[R] liquid are available.
TETRACAINE 0.5% OPHTHALMIC SOLUTION, 15 ml Discontinued due to low use. Tetracaine 0.5% ophthalmic solution, I ml is available.
TRIPLE SULFA VAGINAL CREAM Discontinued due to low use. Metronidazole vaginal cream (Metrogel[R]-Vaginal) is available.
Title Page