This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Ryan, M. Articles by Loprinzi, C. L. Search for Related Content PubMed PubMed Citation Articles by Ryan, M. Articles by Loprinzi, C. L.

As-Needed Morphine: Yes, but at What Dose and at What Interval?

From the Department of Medicine and Department of Oncology, Mayo Clinic, Rochester, MN

Address reprint requests to Charles L. Loprinzi, MD, Division of Medical Oncology, Mayo Clinic, 200 First St SW, Rochester, MN 55905; e-mail cloprinzi{at}mayo.edu

INTRODUCTION

In response to a clinical case of a patient with severe pain requiring large doses of morphine, a question arose about the appropriate dose and schedule of as-needed (PRN) rescue morphine. After receiving varied local opinions, this question was investigated further by providing the following case scenario to several clinicians recognized for their expertise in pain management.

Mrs Smith is an elderly woman with advanced, incurable cancer. She has recently been requiring large doses of morphine to control her pain. Her oral morphine dose for the last 2 weeks has been 1,000 mg of sustained-release morphine every 8 hours (a total of 3,000 mg/d). She has not had any undue toxicity from this dose. She is awake and alert and her constipation is controlled with appropriate laxatives. During the previous 2 weeks, she has developed exacerbated pain with an average daily pain score of 8 of 10. It is decided to admit her to the hospital and give her parenteral morphine to improve her pain control. For this exercise, assume that an appropriate evaluation was done, and no treatment other than narcotics is deemed necessary.

After admitting her to the hospital, the attending physician calculates that she ought to have a 50% increase in her morphine equivalent dose. This equates to 4,500 mg/d of oral morphine. It is decided to translate this into an intravenous dose by dividing this by one third. This is calculated to be 1,500 mg/d of intravenous morphine. It is opted to administer this as a continuous intravenous morphine infusion of 60 mg/h. Because the physician is working with an experienced group of oncology nurses with hospice experience, and the physician plans to leave the hospital grounds (and will be available by pager for questions and emergencies, of course), she decides to order a PRN morphine dose for uncontrolled and/or breakthrough pain. She asks you for advice.

The following two questions were asked of the experts: (1) What is the most appropriate intravenous bolus morphine PRN dose that should be given to this patient in the event that she still has severe pain (with a pain score of 7 to 8 of 10)? ___ mg. (2) At which intervals can this PRN morphine dose appropriately be repeated, assuming that the patient still has uncontrolled pain? ___ 10 minutes, ___ 15 minutes, ___ 30 minutes, ___ 60 minutes, ___ or other, please describe _____________________.

The expert clinicians listed in Table 1 replied; their responses are listed in Table 2

Breakthrough pain can be defined as a transitory increase in pain to greater than moderate intensity occurring on a baseline of pain of moderate intensity.²³ Although breakthrough pain has some similarities to incident pain, they are distinct entities; this current project deals only with breakthrough pain. There have been few studies performed estimating the prevalence of breakthrough pain in patients with cancer. However, in one prospective study of a population referred to a pain service at a comprehensive cancer center, it was shown to occur in 63% of patients.²³ Another study of patients on an inpatient teaching service reported that 50% of the patients had experienced breakthrough pain in the previous 24 hours.²⁴

Treatment of breakthrough pain is universally accepted by pain experts as being an important component of an effective pain management regimen. The goal of such an approach should be to allow the quickest relief of pain, safely. It is evident, however, from both the above-performed exercise and the review of the literature, that there is considerable debate regarding the appropriate dose and dosing interval for the treatment of breakthrough pain. This wide variability in expert opinion likely contributes to the discomfort physicians have in managing cancer pain.

Two key components regarding breakthrough pain treatment relate to the amount of the dose and the timing interval of the subsequent PRN dose. A larger breakthrough dose is more likely to be effective but at the risk of increased adverse effects, whereas smaller dosing increments may lead to inadequate treatment of pain, resulting in a delay in adequate pain relief. Dosing intervals that are too short do not allow for adequate determination of the effect of the previous dose, increasing the risk of adverse effects. Longer intervals between available doses lead to a delay in achieving adequate pain relief.

The median recommended dose in the literature review (when noted), in terms of a percentage of the total scheduled daily dose, is 10% (mean, 9%). In comparison, the median dose mentioned by the questioned experts was 4% (mean, 4%), even though many of them provided formulas that recommended that the PRN dose should be 10% to 20% of the total daily dose. It is presumed that the lower recommended dose in the presented case is due to the very large narcotic doses needed in this patient, despite a lack of literature to support such a tactic.

Little information has been available regarding the safety of giving large doses of intravenous morphine for breakthrough pain. Nonetheless, a recent publication has addressed this issue.²⁵ This study evaluated the safety and efficacy of intravenous morphine for breakthrough pain in 48 patients (171 breakthrough pain episodes) who were given bolus (during 5 minutes) morphine doses at a level of 20% of their total daily morphine dose. Patients in this study had basal total morphine doses up to approximately 800 mg/d. Ninety-four percent of patients had more than a 33% reduction in their pain scores within 17 minutes. Toxicities were judged to be relatively mild, considering the severe pain that patients were experiencing, with moderate to severe nausea/vomiting observed in 7% of episodes, moderate to severe drowsiness observed in 15% of episodes, and moderate to severe confusion observed in 1% of episodes. The occurrences of these toxicities did not appear to be related to individual patients' basal morphine doses.

Another recent report²⁶ suggested that PRN intravenous narcotic doses, instead of being given as a bolus, might better be given as a short infusion. This might increase the comfort of physicians and nurses by giving them the ability to observe the patient closely during a 15-minute infusion, and providing the assurance that the infusion could be stopped if the patient developed toxicities during the infusion time.

A shorter timing interval for subsequent doses allows for better patient flexibility and quicker titration in managing severe pain exacerbations. However, timing intervals less than the time to peak effect increase the risk of overdosing and adverse effects. The best interval for dosing breakthrough medicines should balance these factors. The median timing interval for repeat doses by the surveyed experts was 10 minutes (mode -10 minutes). Data from the recent study by Mercadante et al²⁵ revealed that in 171 breakthrough pain episodes, the time needed to reach the targeted pain intensity was within 15 minutes in 39% of episodes, and within 30 minutes in an additional 56% of episodes.

On the basis of the above-described data, for a breakthrough morphine dose, it appears reasonable to use 10% to 20% of the total daily morphine dose. This dose could be given either as a bolus during 5 minutes or as a short infusion during 15 minutes. Doses could be repeated after 10 to 15 minutes if given as a rapid bolus, or 15 minutes after the completion of a 15-minute infusion (ie, a total of 30 minutes between initiation of doses). In addition to using this approach in patients with pain related to advanced cancer, consideration of studying a similar approach is reasonable in patients with other types of pain, such as postsurgical or procedural-related pain

If the above information is applied to the outpatient setting when oral morphine is being used, it again appears reasonable to use a breakthrough morphine dose of 10% to 20% of the total daily dose. Given that oral morphine takes up to 60 minutes to achieve peak effect,²⁵ repeat dosing is reasonable at 1-hour intervals assuming there is inadequate pain relief and no toxicity.

Specific guidelines for prescribing opioids are needed to allow practitioners to feel comfortable in administering these medications. These guidelines must include how to determine the appropriate dose for breakthrough pain, and the appropriate and safe interval that will allow for rapid pain relief, but maintain patient safety. On completion of this project, the 2004 National Comprehensive Cancer Network guidelines for cancer pain were found.²⁷ These guidelines come to similar conclusions that recommend the use of intravenous narcotic doses of 10% to 20% of the daily intravenous morphine equivalent and the use of repeat doses at 15-minute intervals, if pain is still present. The information from this project might be used to facilitate continuous-improvement projects at individual institutions. Such a project is in process locally. The incorporation of this new information regarding PRN narcotic use should better serve the needs of patients.

Authors' Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

NOTES

Authors' disclosures of potential conflicts of interest are found at the end of this article.

REFERENCES

1. Hanks GW: Morphine and alternative opioids in cancer pain: The EAPC recommendations. Br J Cancer 84:587-593, 2001[CrossRef][Medline]

2. Citron ML, Johnston-Early A, Fossieck BE Jr, et al: Safety and efficacy of continuos intravenous morphine for severe cancer pain. Am J Med 77:199-204, 1984[CrossRef][Medline]

3. McDonald N: Oxford Text. Oxford, United Kingdom, Oxford University Press, 1993, pp 262-263

4. Jacox A, Carr DB, Payne R: New clinical-practice guidelines for the management of pain in patients with cancer. N Engl J Med 330:651-655, 1994[Free Full Text]

5. Grossman SA, Sneidler VR: Clinical oncology 1995 clinical oncology, in Ableoff MD, Armitage JO, Lichter AS, et al (eds): New York, NY, Churchill Livingstone, 1995, pp 363

6. Levy M: Pharmacologic treatment of cancer pain. N Engl J Med 335:1124-1132, 1996[Free Full Text]

7. Ashburn M, Rice L (eds): The Management of Pain. New York, NY, Churchill Livingstone, 1998, pp 478-479

8. Raj PP (ed): Practical Management of Pain (ed 3). Chicago, IL, Mosby Year Book, 2000, pp 248-249

9. Devita VT Jr: The Principles and Practice of Oncolgy (ed 6). Philadelphia, PA, Lippincott Williams & Wilkins, 2001

10. Wall P, Melzack R: Textbook of Pain (ed 4). Edinburgh, United Kingdom, Churchill Livingstone, 1994, pp 1479-1491

11. Emanuel LL, von Gunten CF, Ferris FD (eds): The Education for Physicians on End-of-Life Care (EPEC) Curriculum: The EPEC Project, The Robert Wood Johnson Foundation, Chicago, IL, 1999

12. Aspen Group. Palliative Care Manual. Gaithersburg, MD, Aspen Publishers, 1999

13. Physicians' Desk Reference (ed 53). Montvale, NJ, Medical Economics Co Inc, 1999

14. Omoigui S: Sota Omoigui's Pain Drugs Handbook (ed 2). Malden, MA, Blackwell Science, 1999, pp 397-398

15. Abraham SE, Haddox JD: The Pain Clinic Manual. Philadelphia, PA, Lippincott, 2000, pp 316

16. Walsh D: Pharmacological management of cancer pain. Semin Oncol 27:45-63, 2000

17. Waller A, Caroline NL: Handbook of Palliative Care in Cancer. Boston, MA, Butterworth-Heinemann, 1996

18. Loeser J: Bonica's Management of Pain (ed 3). Baltimore, MD, Williams & Wilkins, 2001, pp 674-677

19. Kinzbrunner BM, Weinreb NJ, Policzer JS: 20 Common Problems in Palliative Care. New York, NY, McGraw Hill, 2002, pp 123-125

20. Portenoy RK, Payne D, Jacobsen P: Breakthrough pain: Characteristics and impact in patients with cancer pain. Pain 81:129-134, 1999[CrossRef][Medline]

21. Benedetti C, Brock C, Cleeland C, et al: NCCN practice guidelines for cancer pain. Oncology 11A:135-150, 2000

22. Krakowski I, Theobald S, Balp L, et al: Summary version of the standards, options and recommendations for the use of analgesia for the treatment of nociceptive pain in adults with cancer. Br J Cancer, 89:S67-S72, 2003

23. Portenoy RK, Hagen NA: Breakthrough pain: Definition, prevalence and characteristics. Pain 41:273-281, 1990[CrossRef][Medline]

24. Indelicato RA, Portenoy RK: Opioid rotation in the management of refractory cancer pain. J Clin Oncol 20:348-352, 2002[Free Full Text]

25. Mercadante S, Villari P, Ferrera P, et al: Safety and effectiveness of intravenous morphine for episodic (breakthrough) pain using a fixed ratio with the oral daily morphine dose. J Pain Symptom Manage 27:352-359, 2004[CrossRef][Medline]

26. Davis MP: Acute pain in advanced cancer: An opioid dosing strategy and illustration. Am J Hosp Palliat Care 21:47-50, 2004[Abstract/Free Full Text]

27. Panchal SJ, Grossman SA Benedetti C, et al: Cancer Pain, National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology, version 1, 2004. http://www.nccn.org

Submitted September 24, 2004; accepted January 24, 2005.

This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Ryan, M. Articles by Loprinzi, C. L. Search for Related Content PubMed PubMed Citation Articles by Ryan, M. Articles by Loprinzi, C. L.