Pain Management in Cancer Patients
L. Bressler
November, 1997
OBJECTIVES
1. Discuss factors influencing pain in cancer patients.
2. Discuss the subjective nature of pain.
3. Discuss the possible sites of action of opioid analgesics.
4. Be able to choose an opioid analgesic regimen based upon specific patient concerns (eg. renal function, age).
5. Be able to adjust an analgesic regimen based upon therapeutic response and/or side effects.
6. Discuss common side effects associated with opioid analgesics, and ways to minimize or prevent them.
7. Discuss the role(s) of other, non-opioid drugs in the management of pain in cancer patients.
REQUIRED READING
1. Levy MH: Pharmacologic treatment of cancer pain; N Engl J Med 335:1124-1132, 1996
SUGGESTED READING
1. Reisine T, Pasternak G: Opioid Analgesics and Antagonists, in The Pharmacological Basis of Therapeutics (eds. Hardman, Limbird, Molinoff, Ruddon, Gilman), McGraw Hill, 1996, p.521-555
PAIN MANAGEMENT IN CANCER PATIENTS
I. SUBJECTIVE NATURE OF PAIN
A. Basically, there are two components of pain. The first component is the sensory input to the central nervous system (CNS) that results in recognition of the sensation of pain. Under controlled laboratory conditions, the amount of stimulus required to produce such a sensation (ie. PAIN THRESHOLD) would be very similar in all subjects. However, this sensation, produced outside of a pathological setting, is not "pain".
By definition, pain is subjective. It is defined as a sensory and emotional experience. The second component is the REACTIVE, SUBJECTIVE COMPONENT. It is the reaction to the first component - the meaning or the interpretation of the pain. It is influenced by the setting in which the pain occurs (eg. more fear might be evoked by "crushing" chest pain than by the same quality and intensity of pain in another part of the body) and by the experiences, attitudes and beliefs of the patient. The reactive component varies widely from person to person and it would seem, then, that it is the reactive component that we are dealing with when patients complain of pain, and when we treat pain.
B. ACUTE versus CHRONIC PAIN
Acute pain serves as a warning to patients to seek medical attention. Frequently, acute pain can be "understood", in that one knows the cause. A healing period can anticipated. Such is not the case with chronic pain, especially that due to cancer. It serves no useful purpose and its presence cannot be "rationalized" or "understood". The subjective component is obviously very important in chronic pain due to cancer. Twycross describes this quite well: "Chronic pain differs from acute pain in that it is a situation rather than an event, it is impossible to predict when it will end, it usually gets worse rather than better, it appears to be entirely meaningless and frequently expands to occupy the patient's whole
attention, isolating him from the world around. Consequently, there is a greater likelihood of a negative pain-potentiating psychological component in chronic pain than in acute pain. Depression, anxiety, fear, mental isolation, other unrelieved symptoms, and pain itself will all tend to exacerbate the total experience of pain. To relieve the pain, all these factors must be considered."
There are few or no OBJECTIVE SIGNS of chronic pain. PAIN IS WHAT THE PATIENT SAYS HURTS.
II. OPIOID ANALGESICS are the mainstay for treatment of
chronic pain due to cancer
A. MECHANISM - opioid analgesics exert their effects by binding to opiate receptors.
1. Transmission of pain impulses to the brain may be altered following opioid binding at the receptor.
2. The reactive component of pain may be altered following opioid binding at the receptor. Some areas of the brain rich in opiate receptors are those relating to mood and behavior.
B. GUIDELINES FOR USE
1. For patients with persistent, severe pain, medication on a SCHEDULED BASIS rather than PRN is generally preferred. It is easier to prevent pain from recurring than to treat it once it has recurred. The anxiety component increases as the last dose is wearing off and pain must be experienced before the next dose is given. This exacerbates the pain and makes it more difficult to eradicate with subsequent doses.
2. PO:PARENTERAL RATIO - Due to a first-pass effect, all of the opioids are more effective when given parenterally than when given orally. The ratio of oral to parenteral effectiveness of morphine is reported to be 1:6 (ie. six times the parenteral dose is required to achieve the same effect orally). This and other estimates are based on single dose studies. Chronic oral use seems instead to result in a ratio closer to 1:2 or 1:3. A helpful "rule of thumb" is to use 1:2 or 1:3 as the PO:PARENTERAL RATIO for all opioids, as a starting point. Thus, when switching a patient from oral to parenteral, doses can be halved (or decreased to one-third), and when switching from parenteral to oral, doses can be doubled (or tripled). This "rule of thumb" also makes calculating equianalgesic doses easier - if all of the drugs have a similar PO:PARENTERAL potency ratio, parenteral equianalgesic doses (ie. equivalent to 10mg morphine SQ) can be applied, proportionately, to oral opioids as well.
C. EQUIANALGESIC DOSES
DRUG ROUTES OF ADMINISTRATION
APPROXIMATE EQUIANALGESIC
DOSES*
APPROXIMATE DURATION
codeine PO, parenteral 120mg 4-6 hours hydromorphone PO, parenteral PR
2mg 2-5 hours levorphanol PO, parenteral 2mg 4-6 hours meperidine PO, parenteral 100mg 2-4 hours methadone PO, parenteral 10mg 6-12 hours morphine PO, parenteral PR 10mg 3-4 hours oxycodone PO 15mg 4-6 hours
* parenteral doses equianalgesic to morphine sulfate 10mg SQ
Again, the same equianalgesic doses would apply to oral opioids, if one uses the PO:PARENTERAL potency ratio of 1:2 or 1:3 for all opioids, as mentioned previously. The table of equianalgesic doses provides GUIDELINES for switching from one opioid to another. Determination of equianalgesic doses was not done in patients with chronic pain due to cancer and the doses are approximate.
D. STARTING DOSES -
Common starting doses for opioid-naive patients are shown in the table. These doses are not necessarily equianalgesic. They are determined by experience of the prescriber, dosage forms and sizes available, and individual patient characteristics (eg. patients 70 years or older may start with lower doses of opioid as they may be more sensitive to the therapeutic effect, as well as to side effects).
COMMON STARTING DOSES
OPIOID-NAIVE PATIENTS
codeine 30mg hydromorphone 2mg levorphanol 2mg meperidine 50mg methadone 5mg morphine 10mg oxycodone 5mg
E.
If an opioid is to be started in a patient who is not opioid-naive, the dose equianalgesic to the previous opioid should be estimated. This can be used as a starting point, keeping in mind that the dose might have to be increased (eg. maybe the previous opioid or dose was ineffective) or decreased (eg. maybe tolerance developed to the previous analgesic and there was not complete cross tolerance with the new opioid. See below)
F. CHANGING DOSES -
Similarly, increments in opioid dose are conveniently made taking into account the dosage forms and sizes available. Furthermore, the per cent increase is higher when the doses are lower, and lower at higher doses. For example, consider a patient being started on morphine sulfate solution, 2mg/ml. A common starting dose would be 10mg (one teaspoonful). If 10mg didn't provide satisfactory relief, the dose might be increased 100% - 20mg (two teaspoonsful). On the other hand, in a patient receiving 100mg of morphine, the dose might be increased to 120 or 140mg.
G. MAXIMUM DOSE -
There is no absolute maximum dose of opioids for chronic pain due to cancer. Since tolerance develops to respiratory depression (see below), doses can be increased gradually to maximize pain control. As long as patients are getting some relief, and side effects are at an acceptable level, opioid doses can be increased. When patients are getting no relief, or side effects are greater than analgesic effect, opioid doses should not be further increased. Instead, a new drug should be instituted. Patients may display individual variation in analgesic response to the same drug. Such variation cannot be accurately predicted.
H. DURATION OF ANALGESIC ACTION -
Approximate durations of analgesic action are shown in the table above. Duration of pain relief can vary among individuals, and does not appear to correlate well with half-life. In general, the only "long acting" opioid is methadone, which may provide pain relief for six or eight or even twelve hours. It is not unusual for patients taking "short acting" opioids (ie. everything other than methadone or perhaps, levorphanol) to report that pain relief lasts for only three or two or even one hour.
SUSTAINED RELEASE morphine preparations (MS Contin?, Oramorph SR?) and oxycodone (Oxycontin?) have recommended dosing intervals of eight or twelve hours. Kadian? is a sustained release morphine capsule that is indicated for Q 24 hour dosing. These preparations have demonstrated bioavailability equivalent to immediate release products. Since evidence of a blood level-response relationship for morphine in chronic pain is equivocal, it is not clear that this bioavailability truly predicts duration of pain relief. The manufacturers recommend that the dose be increased (rather than the interval be shortened) in the event that the duration of pain relief is inadequate. Clinically, this does prolong the duration, although the total daily dose may be greater than the previous, immediate release, total daily dose. The long acting morphine capsule reportedly can be opened and the contents placed in food or a feeding tube without destroying the sustained release mechanism.
The duration of respiratory depression (as well as miosis) from METHADONE is considerably longer than the duration of analgesia. The potential exists then, for frequent, repeated dosing with resultant cumulative toxicity. If methadone does not provide pain relief for at least six hours, its use should be re-evaluated since it is not "long acting" in this case. It should not be given any more frequently than every six hours.
Transdermal FENTANYL is marketed for the treatment of chronic pain, with a recommended dosing interval of 72 hours. Clinical observations seem to indicate that the manufacturer's conversion guidelines from other opioids are rather conservative, and that the duration of pain relief may be shorter than 72 hours. Although the place of this preparation in cancer pain therapy is still not clearly defined, it would seem to be useful in select populations (eg. patients who can't take solid oral dosage forms, patients with feeding tubes).
Twycross, reporting on pain management in hundreds of terminally ill cancer patients, also recommends increasing the dose of immediate release morphine when effective analgesia is maintained for less than four hours.
I. MONITORING PARAMETERS
EFFICACY - What degree of pain relief is obtained? How long does the degree of relief obtained last? (ie. duration of analgesia) If the degree of relief is inadequate, an increase in dose may be attempted. If the degree of relief is adequate but the duration is shorter than the prescribed dosing interval, a decrease in interval may be attempted. Alternatively, the dose may be increased to prolong the duration of pain relief, as discussed above.
How OFTEN should efficacy be ASSESSED? Daily might be ideal. In the case of severe pain, efficacy should be assessed following one dose. More practical in an outpatient setting is assessment after several days on a regular dose.
HOW should EFFICACY be ASSESSED? Ask the patient. Remember, pain is subjective. An observer cannot accurately measure pain (or pain relief). A numeric pain rating scale may be useful - either verbal or written. A patient may define an "8" out of 10 as unbearable pain. A decrease to a "3" or "4" may be quite acceptable. Other similar pain assessment scales may also be utilized. OVERALL ASSESSMENTS or GLOBAL ASSESSMENTS made by patients likely take in to account other than just analgesic efficacy. A drug may work very well but if the patient considers the side effects unacceptable, their overall assessment may be negative.
SIDE EFFECTS - Ask the patient about common side effects: CONSTIPATION; SEDATION - Sedation occurs early on and usually improves within several days. New onset of sedation in a patient previously stable on an opioid is unlikely due to the opioid (unless the patient has acutely deteriorated); CONFUSION - Confusion also occurs early on and should improve. Confusion is seen more often with methadone and more often in the elderly.
A. COMBINATIONS -
Remember ASPIRIN and ACETAMINOPHEN in Percodan?, Percocet?/Tylox?, Vicodin? and others. Patients taking acetaminophen 1gm every four hours and not getting adequate pain relief could be switched to another drug so as not to increase acetaminophen. Hepatotoxicity has been reported with chronic regular use of therapeutic doses of acetaminophen.
B.
CONTINUOUS INFUSIONS of opioid (morphine, hydromorphone) - Morphine doses reported have ranged from 1mg to several grams per hour. As is the case with intermittent administration, there is no absolute maximum dose. Continuous infusions benefit patients requiring frequent dosing or patients who can't take medication orally. They have been administered intravenously or subcutaneously. Infusion rates should be controlled by infusion control devices. Several guidelines are available for dosing continuous opioid infusions:
2.5mg morphine IV push every 10 minutes until relief. Then start continuous infusion at an hourly rate equal to the cumulative IV push dose.
Alternatively, start at 1mg morphine/hour with subsequent adjustment based on degree of pain relief and side effects.
Or, for patients on high opioid doses, calculate the 24 hour opioid dose, convert this dose to parenteral (morphine) and then divide by 24 to determine the hourly dose.
C.
Avoid METHADONE in the elderly, in patients with severe liver dysfunction (ie. patients thought to have decreased liver metabolizing capacity) and in patients with compromised pulmonary function. In the latter two groups of patients, the potential exists for cumulative toxicity with methadone.
D.
Avoid MEPERIDINE for chronic frequent use and in patients with renal dysfunction. Meperidine is metabolized to normeperidine which has CNS stimulatory activity and can cause seizures. Normeperidine accumulates in patients with renal dysfunction. However, there are also reports of neurotoxicity in very ill patients (but without renal failure) who received regular, frequent dosing with meperidine. There is some suggestion that CNS toxicity might also occur with FENTANYL, which is structurally similar to meperidine, and is metabolized to norfentanyl. MORPHINE-6-GLUCURONIDE may also accumulate in patients with renal dysfunction or on high doses of morphine. It is thought to contribute the development of myoclonus.
E. HEROIN -
Orally administered heroin is no different than morphine. Indeed, it is metabolized to morphine. Parenterally administered heroin has greater solubility than morphine, thus more drug can be delivered in a small volume. This is important in patients with little or no muscle mass receiving frequent intramuscular injections. Dilaudid HP? offers a concentrated solution of parenteral opioid (10mg per ml), obviating the need for heroin. Newer, more concentrated strengths of morphine are also available for parenteral use.
F. PROPOXYPHENE -
Qualitatively, propoxyphene binds to opiate receptors, resulting in the same effects as other opioid analgesics. Quantitatively, however, propoxyphene is much less potent than other opioids and is commonly considered with non-opioid analgesics. There are some situations in which propoxyphene may be particularly useful: Propoxyphene WON'T MASK A FEVER. Other non-opioid analgesics (aspirin and nonsteroidal anti-inflammatory drugs, acetaminophen) have antipyretic activity. Propoxyphene DOESN'T INHIBIT PLATELET AGGREGATION. Inhibition of platelet aggregation occasionally limits the use of aspirin and many nonsteroidal anti-inflammatory drugs (but not acetaminophen).
IV. SIDE EFFECTS OF OPIOID ANALGESICS
A. RESPIRATORY DEPRESSION -
In equianalgesic doses, ALL OPIOIDS DEPRESS RESPIRATION TO THE SAME DEGREE. Clinically, respiratory depression may be seen as shallow and slow respirations. It has been reported that respiratory depression (decreased rate) was significant when it was accompanied by somnolence. Tolerance develops to respiratory depression, and usually, respiratory depression is not a problem when using opioids for chronic pain due to cancer.
B. NAUSEA and VOMITING -
Opioids produce vomiting by stimulation of the chemoreceptor trigger zone (CTZ). There is also a VESTIBULAR component to GI symptoms, in that nausea and vomiting are seen more in ambulatory than in supine patients. PHENOTHIAZINES may help minimize nausea and vomiting (eg. prochlorperazine 10mg every 4 hours). ANTIHISTAMINES such as meclizine or dimenhydrinate can help minimize the vestibular component. Tolerance also develops to the nausea and vomiting. Symptoms commonly improve within about a week of regular opioid use.
C. SEDATION -
Sedation may be seen with all of the opioids. It is more common in the elderly and with methadone. Tolerance also usually develops to opioid-induced sedation.
D. CONSTIPATION -
Constipation occurs in a significant percentage of patients receiving opioids. Tolerance does not appear to develop to constipation. Regular use of stool softeners or bulk laxatives may minimize constipation. However, stimulant laxatives are often required on a chronic basis.
E. SWEATING/PRURITUS -
Sweating is due to vasodilation, probably mediated by histamine release. Pruritus is also thought to be due to histamine release. Tolerance does not develop to sweating or pruritus. It is reported that fentanyl does not cause release of histamine.
F. SEIZURES -
see above discussion of MEPERIDINE. MYOCLONIC JERKS are sometimes seen with morphine or other opioids, especially at high doses. They appear to be particularly discomforting for caregivers. Benzodiazepines have been used to treat myoclonic jerks.
G.
As is the case with analgesic response, there is UNPREDICTABLE INDIVIDUAL VARIATION IN TOXICITY. When one opioid produces unacceptable side effects, another opioid may be tolerated.
A. NONSTEROIDAL ANTI-INFLAMMATORY DRUGS -
These drugs are commonly used for pain due to BONE METASTASES. It is proposed that PROSTAGLANDINS are involved in the development of bone metastases. Prostaglandins increase the sensitivity of pain receptors (nociceptors) to painful stimuli. Nonsteroidal anti-inflammatory drugs are frequently used in addition to opioids in the management of bone pain.
B. TRICYCLIC ANTIDEPRESSANTS -
In experimental systems, SEROTONIN and DOPAMINE enhance morphine analgesia, and NOREPINEPHRINE antagonizes morphine analgesia. These findings, although not proven in pathologic pain, provide a rationale for the use of tricyclics. Clinically, tricyclics appear to be most effective in the management of PAINFUL NEUROPATHIES (eg. postherpetic neuralgia, infiltration of nerve by tumor).
C. PHENOTHIAZINES -
Based on the above information, theoretically, we might expect phenothiazines to be antianalgesic, as they block dopamine receptors. Probably, any "analgesic" effect is related to sedation, especially in anxious patients. A similar effect is probably seen with ANTIHISTAMINES. BENZODIAZEPINES may serve the same purpose in anxious patients.
D. STIMULANTS -
COCAINE was added to Bromptons mixtures (traditionally, morphine or heroin + cocaine in an alcohol vehicle) to counteract the sedation from the opioid. In recent years, morphine sulfate solution has been found to have efficacy comparable to a Bromptons mixture. Further, with "standard" formulae, the ability to titrate the individual ingredients in Bromptons is diminished. Cocaine may be useful as a local anesthetic in patients with head and neck cancer, when absorbed through mucous membranes rather than swallowed.
DEXTROAMPHETAMINE or METHYLPHENIDATE (5mg BID) may be useful in patients who have intolerable sedation but can't decrease the dose of opioid without compromising the analgesic effectiveness.
E. ANTICONVULSANTS -
PHENYTOIN, CARBAMAZEPINE, and GABAPENTIN, as well as other anticonvulsants, are often used to treat neuropathic pain. They tend to decrease "shoots" in shooting, lancinating pain, not affecting underlying nociceptive pain.
F. MEMBRANE STABILIZERS -
Like the anticonvulsants, LIDOCAINE and MEXILITENE have been suggested to be useful in neuropathic pain.
G.
NMDA antagonists (eg. dextromethorphan) are being studied for pain. Animal data suggests two beneficial effects: prevention of tolerance to the analgesic effect of opioids (see below) and relief of neuropathic pain. Their use is investigational at this time.
VI. TOLERANCE AND DEPENDENCE WITH OPIOID ANALGESICS
TOLERANCE - This refers to an increased amount of opioid necessary to produce the same effect previously seen with a smaller amount of opioid. Tolerance develops to several opioid side effects - RESPIRATORY DEPRESSION, NAUSEA and VOMITING, SEDATION and CONFUSION. Twycross states that tolerance to the analgesic effect is not a clinical problem when opioids are used in chronic pain in cancer patients. When patients require more opioid, their disease can frequently be seen to be progressive. Foley notes that tolerance develops to the ANALGESIC EFFECT and that cross tolerance between opioids is not complete. In either case, side effects permitting, opioid doses can be increased when previous doses are no longer as effective. When switching drugs, the possibility of incomplete cross tolerance may be considered, and a smaller than equianalgesic dose be started accordingly.
PHYSICAL DEPENDENCE implies that a withdrawal syndrome can be seen upon abrupt withdrawal of an opioid or upon administration of an opioid antagonist. Physical dependence is a property of the drug, not the patient. It is generally not a concern in chronic pain in cancer patients. Should the need for opioid be decreased or removed, a withdrawal syndrome can be avoided by tapering the opioid over several days. It has been noted that withdrawal reactions can be prevented if the dose of opioid is 25% of the previous day's dose.
PSYCHOLOGICAL ADDICTION or PSYCHOLOGICAL DEPENDENCE results from a variety of personality, environmental, psychosocial, etc. factors. It does not result from simply exposure to the opioid for a legitimate medical purpose. ADDICTION is NOT A CONCERN AMONG CANCER PATIENTS WITH CHRONIC PAIN.
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