«  Morphine is the strong opioid of choice.

«  Some pains (visceral and soft tissue) respond well to morphine and some (bone, nerve and colic) do not. (see Pain)

Oral morphine should usually be started in a dose of 5mg to 10mg every 4 hours when moderate analgesics are no longer effective. Never prescribe PRN. A laxative and an anti-emetic must be started at the same time.

In titrated doses morphine is an analgesic and does not cause euphoria. Mild drowsiness may occur for the first 2 to 3 days of treatment. The principle is to increase the dose in steps until the patient is pain-free but still alert.

If a patient who is pain-free becomes drowsy, the dose should be reduced. When morphine is used carefully by finding the correct dose for a particular patient’s pain, there are no dangers of needing escalating doses, or of causing respiratory depression.

The myths of tolerance, addiction, and respiratory depression have contributed to the poor management of cancer pain. These myths are based on single dose studies in animals and humans without pain. Chronic pain prevents these side effects. (see below)

MS-Contin (morphine sulfate controlled release) is a very useful drug in terminal care (particularly for home care) when properly administered on a 12-hourly schedule. It is ordinary morphine in a slow release form. Its bioavailability is excellent. (Absorption of MS-Contin may be delayed by a fatty meal.)

It is usually safe to start MS-Contin 30mg every 12 hours for pain, unless the patient is debilitated or elderly. A starting dose of MS-Contin 15mg every 12 hours is recommended for elderly or debilitated patients. (Start MS-Contin 10mg every 12 hours for these patients in countries where 10mg tablets are available.) Start haloperidol 1.5 mg at bedtime simultaneously to prevent nausea. Start a laxative (Peri-Colace or Senokot-S) immediately.

It is usually best to titrate the dose using 4-hourly oral morphine. Once the patient is pain-controlled on a regular 4-hourly dose, then change to the equivalent dose of MS-Contin given every 12 hours. The total dose of MS-Contin over 24 hours is the same as the total dose of 4-hourly morphine. (4-hourly dose of morphine x 3=12-hourly dose of MS-Contin.)

4-hourly dose
of oral morphine

12-hourly dose
of MS-Contin

5 15
10 30
20 60
30 90
45 120
60 180
90 270

Always prescribe MS-Contin on a 12-hourly regime. Increase the dose if pain occurs. A 6-hourly or 8-hourly regime should be avoided, as it can cause episodes of drowsiness due to peaks of absorption. When increasing the dose, it is safe to use the MS-Contin increments shown above. If the patient is pain-free and drowsy, reduce the dose.

In a study of 38 patients switched from oral MS-Contin to the same dose rectally, pain control was maintained in all the patients. The dose range (using 30mg tablets) was between 2 and 10 tablets every 12 hours. The duration of use ranged from 1 to 30 days (mean 11.5 days). None of the patients experienced any local rectal side-effects such as irritation of burning. (Rectal administration of MS-Contin is not approved by the FDA.)

Beware of patients on MS-Contin who have their pain controlled by other means, such as nerve block. The sudden reduction in pain can mean that the patient is getting too much morphine, and this has caused severe respiratory depression. Change to an equivalent dose of 4-hourly morphine before such procedures, and observe the patient carefully afterwards.

When is it wrong to use morphine? It is wrong to use morphine without proper assessment of the pain. Intermittent pains (bone pain, nerve pain, colic) respond poorly or not at all to morphine. Many pains (15%) are not related to the cancer (heartburn, peptic ulcer, anal fissure, etc.) and will not respond to morphine.

Can morphine be started too early?  No. A common fear of doctors is this: “If morphine is started now the patient’s body will develop tolerance. Higher and higher doses will be needed. When pain worsens later, it will no longer be effective.” This does not occur. Used properly in chronic pain, morphine is an analgesic with no properties of tolerance. If the pain is constant the correct dose (the one that controls the pain without causing drowsiness) can remain constant – for weeks, for months, or even for years in some cases. If the pain is reduced, the dose of morphine will need to be reduced. If the pain increases, the dose will need to be increased.

What is the correct dose? The correct dose of morphine is the dose that relieves the pain without causing drowsiness. To find the correct dose, the principle is to titrate – start with a low dose and then promptly increase it until the pain is relieved.

Mr. J.P. has carcinoma of the larynx with metastases in the right cervical nodes. He enjoys going to the pub for a drink in the evenings, but finds that his neck and right shoulder ache. Codeine 60mg every 4 hours has previously relieved the pain, but the ache is getting worse. Mr. J.P. is frightened of starting morphine, saying “It’s only an ache, if it turns into pain I’ll let you know.” Before long, even wearing his heavy tweed jacket makes his shoulder ache, and an alert home care nurse observes that he has stopped going to the pub. He is persuaded to try oral morphine, 10mg every 4 hours. His ache is better, and he is able to go out again in the evenings. In fact, although he is much better, the ache returns about 3½ hours after each dose, and he has about ½ hour of increasing pain before each dose. The dose of morphine is therefore increased to 20mg every 4 hours, and he is completely free of the ache. He is changed to MS-Contin 60mg every 12 hours for the sake of convenience. Mr. J.P. is delighted, and so is the owner of the pub he frequents!

What if the patient gets drowsy?  In any patient on morphine the rule is this: if pain-free and drowsy, reduce the dose. Be sure to exclude other causes of drowsiness (hypercalcemia, for example). (see Drowsiness)

Remember, some pains respond poorly to morphine. Neuralgias, bone pains, incidental pains like tension headaches, anal fissures, abscesses, colics (gut, renal and biliary), and distention pains like gastric distention and tenesmus are among those. Increasing the dose of morphine for those pains will make the patient drowsy without relieving the pain.

Is there a maximum safe dose of morphine?  No. The principle is this: if 4-hourly morphine relieved the pain a bit, increase the dose in steps until the pain is relieved, using the increments of 5mg, 10mg, 20mg, 30mg, 45mg, 60mg, etc. The dose should be increased every four hours if there is still pain. 90% of patients with morphine-responsive pains will have relief within that 5mg to 60mg range, but occasionally, as the case history below shows, the dose may need to be 500mg or higher.

Mr. N.C. is 27, a computer programmer, with a hepatoma. A previous embolization for liver pain had little effect, and his family doctor prescribed oral morphine 10mg every 4 hours. He found that taking a double dose every 2 hours was helping but not abolishing the pain. He was seen at the hospice outpatient clinic, and the dose was increased to 60mg every 4 hours. This abolished the pain, and he returned to work. A week later he was still pain-free, and was changed to MS-Contin 180mg every 12 hours – to make it easier to take as a twice-a-day regime. Three weeks later he again had severe right-sided pain, and was admitted to the hospice. Morphine was re-started at a dose of 90mg every 4 hours and was increased after one dose to 150mg every 4 hours. He was then pain-free, and after 36 hours returned home and went back to work. A week later in the clinic he was complaining of breakthrough pain between doses. The dose of morphine was increased to 300mg every 4 hours, with a double dose (600mg) at bedtime to allow him 8 hours of sleep. On this regime he remained pain-free for 8 weeks, working full time, driving his car, and not feeling drowsy.

«  At higher doses of morphine the incremental increases have to be bigger. (For example, increase straight from 150mg to 300mg 4-hourly. The dose has been doubled, as when increasing from 5mg to 10mg, or from 10mg to 20mg.)

What dose of morphine should you use for the patient with severe pain, when you are unsure of the analgesic history? The principle is to start with a low dose and observe frequently.

Mr. A. U. is 67, is known to have advanced carcinoma of the bronchus, and presents with severe continuous lateral chest pain. He is unable to give a detailed history. His wife says he has been taking a lot of analgesics of various kinds recently, but has never had morphine. We start with a low dose – morphine 5mg IM – and observe. (In severe pain the IM route is initially better than oral medication as it works faster.) After 20 minutes Mr. A.U. still complains of severe pain – give morphine 10mg IM and observe. After another 20 minutes, the pain is easing but still troublesome – another 10mg morphine IM. Mr. A. U. is now pain-free and drowsy. (He may be drowsy at this stage because of previous lack of sleep and exhaustion.) We re-assess the patient 4 hours after the first injection and he is pain-free. He has had 25mg morphine IM, so we prescribe morphine 25mg IM every 4 hours. (if he remains pain-free but drowsy, we reduce the dose.) Mr. A.U. is able to swallow and is not feeling sick (nausea causes gastric stasis and prevents absorption) so we promptly change to oral medication – 50mg morphine orally every 4 hours (twice the IM dose!) and observe.

Which is the best route for morphine? Morphine is effective by all routes: oral, rectal, sublingual, subcutaneous, intramuscular, intravenous. The sublingual dose is equivalent to the oral or rectal dose. When changing from the oral or rectal route to one of the other systemic routes (subcutaneous, IM or IV), cut the dose in half.

IV infusions of morphine are often used if a patient has a permanent indwelling intravenous catheter. This route can be effective (although it may well not be ideal from the patient’s point of view and is rarely used for analgesia in Britain). It has one major disadvantage: tolerance sometimes develops to morphine administered by the IV route (either infusion or bolus). The patient needs higher and higher doses every 1 to 2 hours, and pain can escape control. Transferring such patients to oral morphine, or to morphine by continuous subcutaneous infusion, gives better pain control with lower doses. The reason why tolerance can develop rapidly to IV morphine, but not by other routes, remains unknown.

Morphine Myths

  I. Tolerance
 II. Addiction
III. Respiratory depression

I.  What about tolerance?

Patients commonly fear that tolerance will occur. (“I didn’t take the pain medication in case it doesn’t work later when I’ll need it more.”) This misconception needs to be explained. Tolerance (needing higher and higher doses with diminishing analgesic effect) does not occur when oral, rectal, sublingual, subcutaneous or intramuscular morphine is used to control visceral or soft tissue cancer pain. (As explained above, it may occur in IV use.) The fear of tolerance is based on the clinical mis-use of morphine in pains poorly responsive to morphine, such as nerve pain, bone pain or colicky pain. (Morphine is ineffective for these pains, and the tendency is to give higher and higher doses, which are also ineffective.) In fact, 90% of patients never need more than 60mg of oral morphine every 4 hours, irrespective of duration of use.

The dose of morphine may increase for the first few weeks as the dosage is titrated (starting with a low dose, then increasing). Dose increase is usually of the order of 30% over two weeks. Once a pain is controlled by morphine, the patient can stay on the same dose for weeks or months. The longer a patient is on morphine, the more likely he is to have a decrease in dosage.

Mr. J.M., age 55, with hepatic liposarcoma and liver pain, was well controlled on oral morphine 150mg every 4 hours. On this dose he was pain-free and mentally alert (demonstrated by his ability to complete The Times crossword puzzle each day). After some weeks he noticed some drowsiness, and he had one hallucination (he thought he saw someone sitting on his bed). The dose of oral morphine was decreased to 120mg every 4 hours, and after a few days (because he still felt a bit drowsy) to 90mg every 4 hours. He remained pain-free on this dose until he died 2 months later.

II.  What about addiction?

«  Patients often fear addiction. Patients with chronic pain do not and cannot get addicted to morphine. This is proved clinically by seeing patients whose pain is abolished (with a nerve block, for example) when even high doses of morphine used for several months can be stopped immediately with no withdrawal effects. Patients who are terminally ill still often fear that they may become addicted to morphine. They and their families can be reassured. This cannot happen when morphine is correctly used to control their pain.

Mr. N.C., who was well controlled on 300mg morphine every 4 hours (see case history earlier), had increasingly severe pain. For three weeks he was pain-free on 600mg morphine every 4 hours, but he then needed a further dose increase to 1000mg morphine every 4 hours. At this point a celiac plexus nerve block was performed for pain control and this abolished his pain. He stopped all morphine the same day and he suffered no withdrawal effects (proving he was not addicted despite the high doses).
A month later he suffered a different pain, this time due to an ileofemoral thrombosis in his left leg. Morphine was started while he was in the hospital for monitoring of anti-coagulant therapy, and the dose was gradually increased to 60mg every 4 hours. This dose controlled the pain for 2 to 3 hours, and he was told (wrongly) that higher doses could not be given. On returning to hospice care his morphine dose was increased to 150mg every 4 hours, and his pain was controlled. After a week his pain decreased as the thrombosis resolved and he became drowsy. Morphine was decreased to 100mg every 4 hours. He remained pain-free and alert until his death 10 days later. Mr. N. C. had not developed tolerance to morphine. A different pain required a different dose.

What about narcotic addicts? Known narcotic addicts with cancer pain respond normally to morphine. The dose is titrated, and the  pain is controlled. The regular use of oral morphine to control pain does not have any euphoric effects (which usually occur only after an IV bolus of a relatively high dose).

Morphine should never be withheld from a patient with proven cancer “in case the patient is a narcotic addict”. If the patient is pretending to have pain in order to get morphine for his addiction, then oral doses every 4 hours will bring no satisfaction, which will be clinically obvious.

III.  What about respiratory depression?

«  Respiratory depression does not occur when morphine is correctly used to control pain.

In one study of 20 cancer patients (12 with COPD) taking at least 100mg of morphine per day for at least 7 days, only one had an elevated pC02 level. As long as morphine is titrated, and the dose is reduced if drowsiness occurs, there is no danger of respiratory depression. Following pain relieving procedures (such as a nerve block), morphine should be stopped. If pain persists morphine should be promptly restarted in low dosage and titrated.

What about drug interactions? Morphine can be safely prescribed with all other drugs except monoamine oxidase (MAO) inhibitors, which are occasionally used as anti-depressants. Hypertensive crisis or mental excitation can occur.

What about morphine and alcohol? It is safe to have an alcoholic drink. Many patients taking morphine enjoy their accustomed cocktail each evening. In fact, most British in-patient hospices have a small bar or a drinks trolley for just that purpose!

The author and publisher have taken precautions to ensure that the information in this book is error-free. However, readers must be guided by their own personal and professional standards of good practice in evaluating and applying recommendations made herein. The contents of this book represent the views and experience of the author, and not necessarily those of the publisher.

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