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PAIN MANAGEMENT: Medical Management
For decades, the World Health Organization’s Committee on Cancer Pain Relief and Palliative Care
endorsed a three-step analgesic ladder approach to the pharmacologic management of chronic cancer pain.
The model recommended non-opioids for mild pain, weak opioids for moderate pain and strong opioids for
severe pain. This was the gold standard since 1986, but is no longer followed by most pain management
experts. Several years ago, the American Pain Society endorsed a new model of prescribing opioids
immediately for chronic pain followed by careful assessment and addition of adjuvant analgesics including
anti-inflammatory medications and neuropathic pain adjuvants as needed. The belief in getting the opioid on
board as quickly as possible to bring the pain under control was paramount. And yet, all principles of the old
three-step ladder have not been thrown away.
It is still important to dose opioids routinely in order to saturate opioid receptors continuously and prevent
ascending tracts from carrying the pain signal from the periphery to the CNS. Of course, pain regimens must
be individualized to the specific needs of the patient. Now it is acknowledged that not all pain medication be
delivered by the oral route and that the ladder should not be followed rigidly. Breakthrough medications for
pain which is not completely controlled by baseline routine medication must be provided.
What should be done with the old Step-Two Weak Opioids?
As is the case with the three-step ladder, these medications should be removed from our prescribing habits
for persistent chronic cancer pain. There are many problems associated with them that we need to discuss.
First, what is a weak opioid anyway? Well, it is generally assumed that it is weaker than a strong opioid,
right? But this is frequently not the case. Both hydrocodone (the active ingredient in Vicodin and Lortab) and
oxycodone (the opioid in Percocet and Percodan) are known to be just as potent as morphine. Morphine has
never been and never will be considered a weak opioid. Codeine, on the other hand, is definitely a weak
opioid. It does not cross the blood-brain barrier and thus cannot bind to opioid receptors and relieve pain
until it is metabolized to morphine in the liver. The enzymatic conversion in the liver is the limiting factor.
Some individuals lack this entire enzymatic process and in most others the enzymatic apparatus is
overwhelmed by any more than 120mg of codeine (two Tylenol #4 tablets every four hours.) Dosing codeine
higher than this will result in no additional conversion to morphine, the codeine will not cross into the brain
and will circulate systemically binding primarily to receptors in the gut and increasing constipation.
Propoxyphene, another step-two weak opioid, found in Darvocet-N-100, and Darvon has been found to be
no better than placebo in many trials. Patients do like propoxyphene, however, for its limbic system
stimulation and the resulting euphoric effects. It is worthless for treating pain.
The greatest problem with this group of medications, however, rests in the fact that most of them are
compounded with acetaminophen (Tylenol.) Obviously Tylenol #3 and Tylenol #4 as well as the previously
mentioned Vicodin, Lortab, and Percocet contain large amounts of acetaminophen. When these medications
are dosed at every four hour intervals (the effective duration of the opioid in each) the total Tylenol
accumulated dose approaches or exceeds generally recognized toxicity limits of four grams per day.
However, in patient’s with already compromised hepatic function due to disease, this safe limit is much lower
and toxicity may realistically occur at doses in excess of two grams per day.
The compounding of these opioids with Tylenol severely limits our ability to prescribe adequate doses of the
opioids, and it is often better and recommended to instead start pain management with small doses of pure
opioid agonists, not those compounded with acetaminophen.
It is for this reason that the American Pain Society recommends starting with pure opioid agonists in
managing chronic cancer pain.
Pure Opioid Agonists for Managing Chronic Pain
The good news is that we have several different pure opioid agonists to choose from in managing pain. The
five most useful opioids that I frequently prescribe are morphine, oxycodone, hydromorphone, fentanyl, and
methadone. Before beginning to discuss the individual merits of these medications, I feel it is useful to briefly
review principles of opioid administration. For most patients, the most effective regimen will consist of a longacting form of an opioid given routinely for chronic baseline pain supplemented by a shortacting form of the
same opioid prescribed as needed for breakthrough pain. This is done simply because PRN alone means:
Pain Relief Not!
By giving enough medication, often enough and retitrating the dose often to meet individual needs of time,
disease progression and activity tolerance, optimal pain relief can be provided. Remembering that the dose
needs to be individualized and that for any given opioid there is no maximum dose and that the correct dose
is that which provides comfort with minimal side-effects both comfort and quality of life may be achieved.
For ease of remembering and dividing opioids by similarities, I group them into two separate categories—
those that are hydrophilic (water soluble) and those that are lipophilic (fat soluble). The hydrophilic group
includes morphine, oxycodone, and hydromorphone while the lipophilic group contains fentanyl and
methadone.
In the past, morphine was considered to be the gold standard of opioid therapy for pain. This is no
longer the case. Toxicity (mental status changes, somnolence) based on metabolites (morphine- 3glucuronide and morphine-6-glucuronide) has made its prescribing problematic in some patients.
Because the potent metabolite M-6-G (often 10x potent as morphine) is manufactured in the liver and
excreted by the kidney, elderly patients with intact livers and compromised renal function require much
smaller doses than average adults (5mg instead of 30mg). Morphine is available in two long acting capsular
forms whose contents can be sprinkled and administered in pudding or apple sauce or down PEG tubes
(Kadian, Avinza.) Oxycodone before the OxyContin scandal had the advantage of being largely unknown by
the general public. There was little or no paranoia associated with the name and patients were willing to
accept it when prescribed. Although this advantage was lost with the publicity surrounding it’s illicit use and
abuse, oxycodone remains a viable choice among the hydrophilic opioids. It’s lack of metabolites gives it an
advantage over morphine in that it is less toxic. It’s “normal release” or short acting form is equal in potency
to morphine. The relative potency of OxyContin, although controversial, seems to be one and one half times
that of morphine in my experience. Hydromorphone (Dilaudid) has been the most potent of the hydrophilics.
This gives it an advantage when administered in subcutaneous infusions where concentration and flow rate
limit the dose of administration. With the recent release of a long acting form (Pallidone which is also able to
be sprinkled) it joins the other two hydrophilic opioids in having both long and short acting forms available.
All hydrophilic opioids in their natural state have peak effects one hour after oral administration and a half-life
of approximately four hours. This means that breakthrough dosing of the naturally occurring short acting
products should be allowed routinely every one hour as needed. For example, a breakthrough dose taken 90
minutes earlier will provide no additional pain relief to a patient and if pain persists at that time another dose
needs to be given. It is therefore irrational to dose prn breakthrough doses at any less frequency than every
hour.
Every two, three, four, or even six hour dosing will not allow the patient to self-administrator medication
frequently enough to guarantee pain relief. On the other hand, we do not want the patient to overdose by
taking medication every hour of the day. For this reason, I usually insist the patient limit him or herself to six
doses per twenty four hours calculated to allow them to double the baseline dose of the long acting opioid
they are taking for baseline pain. If they need more, they are instructed to call me for a dose adjustment.
Lipophilic opioids include fentanyl and methadone. We will discuss fentanyl here and save methadone for
our discussion in the next newsletter about adjuvants and neuropathic pain. Fentanyl is the shortest-acting
opioid on our list. For years it has been given by anesthesiologists post-operatively to guarantee good pain
management during the transition from the operating room to recovery. The thinking was in part that
because it was so short acting it would not impair respirations in the immediate post-operative period.
Most of us are familiar with fentanyl prescribed for chronic pain management in the form of the Duragesic
patch. The patch consists of a unique transdermal delivery system that supplies fentanyl to a subcutaneous
tissue reservoir. Subcutaneous fat is not critical, only adequate systemic circulation to subcutaneous
capillaries so that the fentanyl may find its way to the brain. The duration of action is usually 72 hours but
high output states such as fever may increase the rate of uptake in the capillary bed, accelerating the rate of
absorption across the cutaneous barrier. Observation is necessary to determine those patients likely to
experience rapid uptake in order to make appropriate dose adjustments (most often changing the patch
every 48 hours instead of every 72 hours.)
Because transdermal fentanyl is a very long-acting delivery system with over twenty-four hours required to
reach steady state, patients who require rapid titration of opioids should be treated using different delivery
systems. The transdermal system is excellent, however, with patients who have stable pain and difficulty
swallowing. Duragesic is available in strengths of 25, 50, 75, and 100mcg/hr. The 25mcg patch is
equaivalent to 50mg of morphine per day which may be a high dose for some elderly patients.
Another form of fentanyl, Oral Transmucosal Fentanyl Citrate(Actiq), is available for breakthrough pain.
Dosed by turning and rubbing the unit against the oral mucosa, this medication reaches the brain quickly and
is ideal for managing breakthrough pain in adults. It’s multiple dosage strengths and the need for
individualized titration may limit it’s use somewhat.
What do I do when one opioid is not working or limited by side-effects?
Opioids are idiosyncratic. Simply put this means that some patients will do very well on some, yet be
miserable taking others.
For this reason, we must have skill in switching from a problematic opioid to one that will better manage the
patient’s specific needs. This switching is formally called opioid rotation. In order to successfully rotate from
one opioid to another, several steps are involved. First, knowing the individual properties, advantages and
disadvantages of common opioids as just discussed may help in the selection process. Crossing from the
hydrophilic group to the lipophilic group may really help, particularly changing to methadone.
The first step after selecting the opioid to rotate to is to look at an opioid equianalgesic dosing chart. The one
included in figure 2 is the one I recommend.
After you have calculated the equianalgesic dose, you are not finished. Because of the existence of
incomplete cross-tolerance in rotating opioids, you must reduce the starting dose of the opioid you are
rotating to because the patient is not tolerant to that opioid. In other words, because the patient has
developed a tolerance to morphine over a period of time, when switching to oxycodone the patient will not be
tolerant to that. The dose needs to be reduced.
As a standard, the dose of the opioid you are rotating to needs to be reduced by fifty percent. If the patient is
having intolerable side effects like myoclonus, you may need to start with only twenty-five percent of the
equianalgesic dose of the new opioid in order to avoid toxicity. Remember to provide adequate breakthrough
dosing to compensate for any lack in total opioid dose requirement so the patient may comfortably rescue
themselves from unrelieved pain.
Well, if you’ve read and followed all of this, I think you have had enough for now. Next time we will explore
adjuvant medications for pain including anti-inflammatory medications and neuropathic adjuvants and if time
allows new exciting information about methadone.
Opioids rarely cause delirium. Pain is actually more of a risk factor for delirium than the pain medication11.
Patients who have had chronic pain are often sleep deprived. When their pain is finally relieved with the start
of an opioid, the patients often sleep for 24 to 48 hours straight. This sleeping often alarms the family or
nurse and is misinterpreted as opioid sedation. True opioid sedation can be distinguished from sleep
deprivation by attempting to wake the patient. If the patient is arousable and conversant, they are not
sedated by the opioid. The danger of too readily blaming the opioid is missing or delaying the opportunity to
identify the true underlying cause in addition to unnecessary pain and suffering.
Patients will develop tolerance to the sedating effect of opioids generally within 2 to 3 days of either starting
or increasing the dose. Neurotoxicity from opioids can occur through renal metabolites. This toxicity generally
occurs in older patients or patients with impaired renal function who are on high doses of opioids for a
sustained period of time. Myoclonus usually occurs before the mental status change. The diagnosis can be
made through opioid rotation [changing to an opioid that does not have a renal metabolite, such as
hydromorphone (Dilaudid), oxycodone or Methadone] rather than stopping the opioid.
Risk factors are characteristics that predispose but do not cause delirium. Most of the risk factors are related
to decreased reserve of the brain. Older age is the most common risk factor. Another strong risk factor is
dementia with certain dementias such as Lewy Body disease being more predisposed to psychosis. Any
central nervous system disease (Parkinson’s, Multiple Sclerosis, prior stroke) is also a risk factor for delirium.
Either sensory deprivation or sensory overload can precipitate delirium, and both can occur in the intensive
care unit. For example, even healthy young people when placed into a sensory deprivation tank become
delirious in 2 to 3 days and start hallucinating.
Finally sleep deprivation or disturbance is often related to sensory deprivation or overload and is commonly a
factor that perpetuates the delirium.
INTERVENTIONS
Interventions maybe pharmacological or non-pharmacological. Non-pharmacological ones are preferred,
because they are generally more effective and have less side-effects. Having a sitter or a family member
provide orientation is the best but not always practical or cost-effective.
Other re-orientation techniques, including simple exposure to sunlight or stimulating activities during the day,
will also help to reverse the sleep-wake cycle disruption.
A moderate amount of stimulation such as soothing music is preferred. Catheters, tubes, lines, and even
pneumatic compression stockings should be minimized, and their necessity reassessed. Restraints usually
lead to increased agitation in patients who are confused and do not understand why they are restrained.
They make the patients more paranoid and do not make them safer or reduce falls. In fact, restraints may
increase falls and trauma, such as suffocation, restraint burns, and fractures. For patients at risk for pulling
out tubes and lines, mittens or handrolls (towels or bandages taped into the palms of a clawed positioned
hand) are better than wrist restraints. If the tube or line cannot be removed, then “restraining” the tubing with
netting, an adhesive pad, and bandage is better than restraining the patient. Several pharmacological
interventions are available. First line agents are antipsychotics.
One study, prior to the advent of the newer atypical antipsychotics, showed no difference in efficacy of
various antipsychotics12. A more recent study
comparing risperidone and haloperidol also showed no difference13. The doses are usually lower than those
used for schizophrenia. Older patients may require even less. Extrapyramidal sideeffects rates are low for
several reasons, including that lower doses used, the fact that delirious patients are already cholinergically
deficient in their brains compared with the higher dopamine activity, and that the antipsychotic is used short
term. For patients with Parkinson’s syndromes and Lewy Body dementia, Seroquel is the antipsychotic of
choice as it will not worsen the Parkinsonian symptoms.
The choice of an antipsychotic is otherwise based upon practical considerations and side-effect profile. A
sedating antipsychotic may be more desirable if the patient is agitated or has insomnia. Haloperidol is the
most commonly used in hospice setting because it can be administered in many ways: intravenous, oral,
sublingual, subcutaneous infusion, or even rectally if necessary. Thorazine is an alternative choice if
sedation is desired.
Benzodiazepines are second line agents due to the paradoxical response previously mentioned. This
paradoxical response is less likely to happen if the patient is already on an antipsychotic. Thus if an agitated
patient is still not adequately managed on an antipsychotic, a benzodiazepine can be added for more
sedation.
While lorazepam (Ativan) has traditionally been the choice of hospice agencies, its cost outweighs the mild
benefit difference from other benzodiazepines. Diazepam or Valium is actually faster acting than lorazepam,
and its longer duration may be an advantage. It also can be administered as a concentrated liquid
sublingually or buccally. Third line agents are anticonvulsants such as Depakote and Tegretol. These “mood
stabilizers” are often tried as a last ditch effort. In dementia patients, cholinesterase inhibitors, such as
Donepezil (Aricept) have been suggested to improve behaviors even when they are no longer effective for
cognition14.
When all else fails, palliative sedation is an ethical option and should be offered and discussed with the
family or surrogate decision maker. This sedation can be achieved with a high dose benzodiazepine infusion
such as midazolam (Versed) intravenously or subcutaneously or (lorazepam) Ativan subcutaneously. For
older patients sedation with Phenobarbital or Pentobarbital may be safer and more effective. The barbiturate
can be administered intravenously, subcutaneously, as a liquid through a feeding tube, orally if the patient is
still able, or as a rectal suppository.
CONCLUSION
Delirium is a common problem for patients at the end-stages of their lives. Delirium, particularly the quiet
form, is often unrecognized or under-recognized.
This under-recognition results in a missed opportunity to prevent the agitation that will eventually occur from
the fluctuation inherent to delirium and improve the quality of life for the patient and family member/caregiver.
While most cases of terminal delirium are not reversible because of its multifactorial nature, easily reversible
causes should not be missed. Non-pharmacological interventions are better, but pharmacological
interventions are usually necessary.
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