Boluses

Boluses

"A bolus is like a suppository, used either vaginally or anally. Dr Schulze created a bolus of Squaw Vine herb, Slippery Elm Bark, Goldenseal root, Yellow Dock root, Comfrey root, Marshmallow root, Chickweed herb, Mullein leaf, Garlic bulb and Coconut and Tea Tree oil. Some boluses can be made into suppositories by mixing the materials and placing them into the freezer. These would be used for cervical problems."


INTRAVENOUS MORPHINE FOR EMERGENCY TREATMENT OF CANCER PAIN

Abstract: Despite the wide use of the World Health Organization (WHO) analgesic ladder for the relief of cancer pain, it is not uncommon to find patients presenting with severe pain to palliative care centres. This is more so in the developing world, where facilities for pain relief are few and the health care system is not well organized. It has been the practice in a pain and palliative care clinic in south India to give repeated boluses of 1.5 mg of morphine intravenously every 10 min to patients presenting with severe pain. An audit of the procedure was undertaken by a retrospective study of 793 case notes. Seventy-nine per cent of patients had total relief of their pain with intravenous morphine. Three per cent of patients experienced side-effects during the procedure. These included nausea and vomiting, itching, giddiness, restlessness, dyspnoea, chest pain, disorientation and a feeling of uneasiness. Thirty-two per cent of patients had drowsiness, which was one of the end-points of the procedure. It is concluded that intravenous morphine in repeated boluses of 1.5 mg every 10 min is a safe and effective method of managing cancer pain emergencies in a clinical setting in a developing country.

Key words: administration, intravenous; analgesia; developing countries; morphine; neoplasms; pain; palliative care
Resume: Malgre la large utilisation des paliers antalgiques de I'OMS dans le traitement de la douleur cancereuse, il n'est pas rare de recevoir dans les centres de soins palliatifs des patients presentant des douleurs intenses. C'est encore davantage le cas dans les pays en vole de developpement ou les outils de prise en charge de la douleur sont peu nombreux et le systeme de sante real organise. Dans un centre de soins palliatifs et traitement de la douleur au sud de I'lnde, des patients se presentant avec des douleurs severes ont recu des bolus intraveineux toutes les 10 min de 1.5 mg de morphine. Un audit du protocole a ete realise par une etude retrospective sur 793 cas. Soixante dix neuf pour cent des patients ont ete totalement soulages de leur douleur par la morphine. Trois pour cent des patients ont presente des effets secondaires durant l'application du protocole, a type de nausees-vomissements, prurit, vertiges, agitation, dyspnee, douleur thoracique, desorientation et sensation de malaise. Trente deux pour cent des patients ont eprouve une legere somnolence qui etait un point critique de poursuite du protocole. Nous en concluons que l'administration de bolus intraveineux de 1.5 mg de morphine toutes les 10 min est une methode sure et efficace de prendre en charge les urgerices douloureuses dans le cadre d'un centre de soins en pays en vole de developpement.
Mots-cles: vole intraveineuse; analgesie; pays en vole de developpement; morphine; neoplasies; douleur; douleur; soins palliatifs

Introduction

About 80% of patients with cancer experience pain,[ 1, 2] which can be chronic and severe. The World Health Organization (WHO) has devised guidelines for the analgesic management of cancer pain. These guidelines have been validated in clinical use.[ 3]

Of the estimated nine million new cancers in the world every year, more than half are in the less developed countries. Facilities for pain relief for these patients are either nonexistent or few and far between. The WHO analgesic stepladder is not routinely used by doctors in developing countries. The health care network is also often unable to offer regular follow-up of patients. Pain relief units therefore see a large number of patients who present with excruciating pain of weeks or months in duration.

In the city of Calicut in the south Indian state of Kerala, the Pain and Palliative Care Clinic now sees about 2000 new patients every year. More than 80% of the patients are people with advanced cancer. Many of these are in severe pain. It has been routine practice in this unit to give repeated boluses of intravenous morphine for the relief of severe pain. Over the first 53 months of its existence (January 1994 to May 1998), the clinic saw 4783 new patients, of which 3808 had advanced cancer. Boluses of intravenous morphine were given to 1478 patients. As a measure of clinical audit, we considered it necessary to review the results.

Materials and methods

We performed a retrospective analysis of case notes of patients with cancer pain who received intravenous morphine in the Pain and Palliative Care Clinic at Calicut. All of them were on irregular nonsteroidal anti-inflammatory drugs (NSAIDs). A few were on an occasional dose of a weak opioid drug. The clinic was using a five-point scale (none, mild, moderate, severe, intolerable) for assessment of pain in the early months, but changed over to a 0-10 numerical scale (where 0 meant no pain and 10 indicated the worst imaginable pain) in June 1995. The following inclusion criteria were decided on for inclusion in the analysis:

a clear mention of the presence or absence of side-effects;

recorded pain scores both before and after the procedure, in one of the scales.

There was clear mention of side-effects and pre- and postprocedure pain scores in the case notes of 793 cancer patients, of whom 491 had pain scores recorded on the 0-10 numerical scale.

Any patient who had severe or intolerable pain on a five-point scale or a pain score of 5 or more on a 0-10 scale was considered for intravenous morphine after initial assessment had ruled out a high likelihood of morphine-resistant pain and any contra-indication to morphine. After obtaining venous access, intravenous metoclopramide 10 mg was given to all patients for prevention of possible opioid-induced nausea and vomiting. Then a 1.5 mg intravenous bolus of morphine was given every 10 min. The dose of 1.5 mg as the size of the bolus was decided as a matter of convenience; the available preparation is a 1 ml ampoule containing 15 mg, which on dilution to 10 ml is 1.5 mg per ml. The end point of intravenous morphine therapy was either total pain relief or drowsiness. 'Drowsiness' in this instance, is defined as sleepiness stated by the patient. Any side-effect was recorded. Once the end point was reached, the patient's condition was re-assessed and appropriate oral drug therapy started. A summary of the protocol is given in the appendix.

Results Pain relief

Of a total of 491 patients with pre- and postprocedure pain charted on the numerical scale, 338 (69%) were male and 153 (31%) were female. The most common group of malignancy was head and neck cancers, which accounted for 30% of the total (Table 1). This incidence conforms to the pattern reported in this part of the world. The youngest patient in this group was 18 years old and the oldest 85 years (Table 2). The sample is representative of the cancer patient population attending the Pain and Palliative Care Clinic.[ 4]

The smallest dose of intravenous morphine given in this series of 491 patients was 1.5 mg and the highest was 60 mg. Out of 482 patients who reached the end-point, 380 had total pain relief (79%). Most of these (94%) had total pain relief with doses in the range of 1.5-15 mg. No patient had total pain relief with a dose higher than 34.5 mg. Six patients got no relief at all, and the procedure was stopped when they became drowsy. Percentage of pain relief for each patient is calculated as:

Percentage of relief = (the difference between pain scores before and after the procedure) x 100/pain score before procedure

The number of patients with percentages of relief at the end of the procedure is shown in Figure 1.
On conclusion of the procedure, 137 patients became sleepy. Of these, 36 were drowsy, but had total relief of their pain. Of the 491, nine patients opted out or discontinued the trial before completion because they were uncomfortable with it (Table 3). This is in addition to one patient who preferred not to have the intravenous line restarted when it got blocked at 70% relief.

In the 491 patients, an attempt was also made to classify the pain as aching, burning, lancinating or pricking in the case of patients who clearly stated the predominant nature of their main or only pain. Forty-five patents out of 61 in the 'aching group', 41 out of 54 in the 'burning group', 14 out of 20 in the 'lancinating group' and 162 out of 202 in the 'pricking group' had total pain relief for pain with intravenous morphine. There was no statistically significant difference in the percentage of patients getting total relief for their pain between the four groups (X[ 2] test, P = 0.561).

Side-effects

Of the 793 patients whose case notes showed a clear mention of presence or absence of side-effects, 487 had none (Table 4). Nausea and vomiting were the most common side-effects, which occurred in seven patients, all responding to an intravenous injection of an additional 5 mg of metaclopramide. Giddiness occurred in five patients, lasted from a few minutes to 2 h, and settled on its own. Generalized itching in five patients responded to parenteral chlorphenamine maleate.

Three people complained of breathlessness. One of these (with bronchogenic carcinoma) complained of breathlessness following 1.5 mg of morphine. Although he gave no history of bronchial asthma, he was found on auscultation to have bronchospasm. This was relieved with nebulized salbutamol.

One patient complained of chest pain but nothing was detected on physical examination. The pain was not suggestive of myocardial ischaemia, and subsided without any intervention.

Out of 793 patients, 256 (32%) were drowsy at the end of the procedure. In 172 patients, this was in association with partial relief and was one of the end points of the procedure. Of the patients who had total relief for pain, 84 (22%) were drowsy at the end of the procedure. All the drowsy patients were alert within 90 min and most in 30 min. In no case did the drowsiness become severe enough to be considered a problem by the patient or the family.

Discussion

Of the cancer patients who reported to the Pain and Palliative Care Clinic, 39% had severe pain. Resorting to the classical WHO ladder would have meant delay of several days before reasonable pain relief was achieved. This is not acceptable as the patients had already suffered so much, and often had a very limited life expectancy. Every single painfree day is invaluable for the patient. If immediate pain relief is achieved, it will take away the sense of hopelessness that the protracted pain will have caused. This will give the person more hope and confidence in the treatment offered. These factors induced us to develop the present protocol for firstline treatment of severe cancer pain.
What constitutes a cancer pain emergency is a matter of opinion. Hagen et al.[ 5] defined it as 'pain intensity of 8 or greater, sustained for at least six hours and escalating over a course of several hours to days'. As most of our patients had been suffering pain for weeks or longer, with its inevitable emotional consequences, we thought it necessary to consider anyone with pain intensity of 5 or greater on the visual analogue scale (VAS) to be in need of immediate relief.
Using 10 min as the interval between two doses of intravenous morphine can be criticized. The peak plasma morphine concentration after intravenous injection of morphine sulphate occurs around 30s.[ 6] However, plasma morphine concentration is known not to correlate well with pharmacological activity of morphine after bolus injection, probably because of a delay in penetration of the blood-brain barrier, and a further delay in receptor binding. Cerebrospinal concentrations of morphine peak 15-30 min after intravenous injection.[ 7] Analgesia has been found to reach a maximum about 15 min after peak brain concentrations of morphine.[ 8] In a study comparing intravenous morphine with placebo, it was seen that the times at which 25% of patients reached 50% pain relief were 6 min (with 10 mg bolus dose of morphine), 15 min (with 5 mg bolus dose of morphine) and 40 min (placebo).[ 9]

An interval of 30-45 min between successive doses would thus have been more scientific, but that would have made the protocol impractical in a busy clinic like ours, which sees between 30 and 60 patients a day. An interval of 10 min between the doses was practical and convenient in a busy outpatient clinic. The one disadvantage with our protocol is that the last one or two doses could often have been unnecessary because the previous dose could have achieved the desired effect had we given it enough time to act. Thus it is possible that the desired effect could have been achieved with 1.5-4.5 mg less than what was given. The observation that about 10% of patients were sleepy when they had total relief for their pain supports this view. While theoretically sound, this argument is of little practical significance. The additional or unnecessary 1.5 mg or even 4.5 mg of morphine caused no serious complication. Of the 256 patients who became drowsy, in no case did the drowsiness last longer than 90 min, or become severe enough to be considered a problem by the patient or the family.

It is possible that we might have underestimated the incidence of side-effects because this is a retrospective study. We are likely to have missed those complaints, which the patient did not bring out voluntarily.

It was interesting to see that the percentage of patients getting total relief with intravenous morphine was similar in the four different groups with different descriptions for the predominant nature of pain (burning, aching, lancinating or pricking). Direct translation of the adjectives from English to the local language (Malayalam) might have failed to capture the exact meaning. Cross-cultural studies on pain in the past have also brought out this problem. Cross cultural studies with the Brief Pain Inventory showed that this simple pain assessment tool worked across languages and cultures, but difference between the different mood words were confusing to patients and only a few were able to complete this linguistically more complex task.[ 10]

The present practice of the authors is to reassess the patients after the intravenous morphine trial, to prescribe an appropriate oral regime and to review again within the following 48 h. The usual parenteral to oral conversion ratio of morphine would not be applicable in this case because the patients are morphine-naive and would require a variable quantity of the drug to build up an adequate blood level. From our experience, we found that an approximate 1:1 ratio (initial intravenous morphine dose:first oral dose) is a good starting point in practice. We found that giving an oral dose approximately equivalent to the necessary initial intravenous dose provides satisfactory ongoing relief in most cases. For example, patients needing 3-6 mg intravenously will be started on 5 mg oral morphine 4-hourly, those need 7.5-12 mg on 10 mg 4-hourly, and so on. It is concluded that intravenous morphine in 1.5 mg boluses every 10 min is a safe and effective method of managing pain emergencies in cancer patients in this setting.

Acknowledgements

Thanks are due to Dr Sandro Pampallona (Evolene, Switzerland) for suggestions, Dr Robert Twycross (Oxford, UK) for comments on the modified draft and encouragement, and to the patients, volunteers and staff of the Pain and Palliative Care Clinic, Calicut for their enthusiastic support.

Address for correspondence: Dr K Suresh Kumar, Pain and Palliative Cae Society, Medical College (PO), Calicut 673008, Kerala, India. E-mail: pain@vsnl.com

Table 1 Diagnostic profile of 491 patients (338 male, 153 female)
Primary malignancy Number

Head and neck 149 (30%)
Lung 85 (17%)
Gastrointestinal tract 91 (19%)
Uterine cervix 33 (7%)
Breast 21 (4%)
Male genito-urinary tract 18 (4%)
Others 94 (19%)
Table 2 Age distribution of 491 patients
Age (years) Number

<20 3
20-30 10
30-40 51
40-50 102
50-60 154
60-70 137
70-80 31
>80 3
Table 3 Intravenous morphine: reasons for patients opting out of procedure
Reason Number

Weakness and uneasiness 2
Feeling breathless 1
Restlessness 1
Chest pain 1
Giddiness 1
Vomiting 1
Restlessness and drowsiness 1
No reason stated 1

Total 9
Table 4 Intravenous morphine: side-effect profile of 793 patients (537 male, 256 female)
Side-effects (not exclusive) Percentage of patients

Nausea/vomiting 0.9
Itching 0.6
Giddiness 0.6
Restlessness 0.5
Dyspnoea 0.4
Chest pain 0.1
Disorientation 0.1
Feeling uneasy 0.1
Drowsiness 32

GRAPH: Figure 1 Response to intravenous morphine
GRAPH: Figure 2 Dose of intravenous morphine for total relief

References

1 Portenoy RK. Cancer pain: epidemiology and symptoms. Cancer 1989; 63: 2298-307.
2 Foley K. The treatment of cancer pain. N Engl J Med 1985; 313: 84-95.

3 Ventafridda V, Caraceni A, Gamba A. Field testing of the WHO Guidelines for Cancer Pain Relief: summary report of demonstration projects. In: Foley KM, Bonica JJ, Ventafridda V eds. Proceedings of the Second International Congress on Pain. Vol 16, Advances in pain research and therapy. New York: Raven Press, 1990: 155-65.
4 Suresh Kumar K, Rajagopal MR. Palliative care in Kerala: problems at presentation in 440 patients with advanced cancer in a South Indian state. Palliat Med 1996; 10: 293-98.

5 Hagen NA, Elwood T, Ernst S. Cancer pain emergencies: a protocol for management. J Pain Symptom Manage 1997; 14: 45-49.

6 Aitkenhead AR, Vater M, Achola K, Cooper CM, Smith G. Pharmacokinetics of single dose IV morphine in normal volunteers and patients with end-stage renal failure. Br J Anaesth 1984; 56: 813-19.

7 Hug CC Jr, Murphy MR, Rigel EP, Olson WA. Pharmacokinetics of morphine injected intravenously into the anaesthetized dog. Anaesthesiology 1981; 54: 38.

8 Dahlstrom BE, Paalzow LK. Pharmacokinetic interpretation of the enterohepatic recirculation and first-pass elimination of morphine in the rat. J Phamacokin Biopharm 1978; 6: 505.

9 Whitheead EM, O'Sullivan GM, Lloyd J, Bullingham RE. A new method for rate of analgesic onset: two doses of intravenous morphine compared with placebo. Clin Phamacol Ther 1992; 52: 197-204.

10 Cleeland CS et al. Culture, language, and cancer pain. In: Jensen, Turner Wiesenfield-Hallin eds. Proceedings of the Eight World Congress on Pain. Seattle: IASP Press, 1997: 47.

Appendix: protocol

Rate the pain on numerical scale.

Select patients with pain rated severe or more on a five-point scale or five or more on a 0-10 scale.
Use the description of pain to rule out clinically obvious opioid-resistant pain.
Perform a quick physical examination to rule out contraindication to IV morphine.
Explain the procedure to the patient and family.
Secure IV access with a scalp vein needle in forearm.

Inject metoclopromide 10 mg slow IV.

Inject morphine 1.5 mg bolus every 10 min until the end-point of either total pain relief or drowsiness, whichever occurs earlier.
~~~~~~~~
By K Suresh Kumar, Consultant in Palliative Medicine; MR Rajagopal, Professor in charge and AM Naseema, Research Assistant, Pain and Palliative Care Clinic, Medical College, Calicut

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