A 74-year-old female was diagnosed with adenocarcinoma of the colon 3 years prior to beginning hospice care. She has known metastases to her liver and pelvis. She complains of a cramping pain in her abdomen and a "deep pain" in her groin. She is currently receiving morphine 10 mg orally (PO) every 4 hours (except when asleep) and acetaminophen 650 mg PO TID. She says that her pain is 4 out of 10 on a numeric pain scale. Her past medical history includes hemorrhage secondary to a gastric ulcer 4 years ago (Helicobacter pylori negative on biopsy).
Question 27.2.1 Which of the following strategies is the best next step for improving this patient's pain control?
A) Start gabapentin to treat the neuropathic aspect of her pain.
B) Add a strong nonsteroidal anti-inflammatory drug (NSAID) such as ketorolac (Toradol) to her current regimen.
C) Add scheduled tramadol to try to decrease her morphine use.
D) Start a long-acting morphine (e.g., MS Contin) at a dose 20% higher than her current morphine use.
E) Maximize the dose of acetaminophen to 1,000 mg every 4 hours.
Answer 27.2.1 The correct answer is "D." The patient is taking short-acting opiates around the clock, which can lead to "chasing the pain" (not to be confused with "chasing the dragon," which is inhaling heroin smoke, which leads to a leukoencephalopathy … you never know … it could be on the test!). Patients often receive much better pain control when they are maintained on a long-acting opiate. It is common practice to increase the dose of opiates by 15% to 25% when a patient's pain is only partially controlled. It is then recommended to have the breakthrough dose equivalent to 10% of her 24-hour use. "A" is incorrect as her pain is better described as visceral or somatic rather than neuropathic. Gabapentin is an acceptable choice for neuropathic pain but is not likely to be effective for this patient. "B" is incorrect. Ketorolac is the NSAID with the highest rate of renal disease and gastrointestinal (GI) bleeds and is contraindicated in a patient who has had a GI bleed. If you were to add an NSAID, ibuprofen would be a better choice, and GI protection with a proton pump inhibitor would be advisable for this patient. "C" is incorrect. Tramadol is a weak mu-receptor agonist, possessing some norepinephrine and serotonin reuptake inhibition and is much less efficacious than morphine. Tramadol is not likely to benefit a patient with severe pain from cancer and metastases. Tramadol also has a number of troubling side effects such as an increased risk of seizures and serotonin syndrome. "E" is incorrect because the current recommended daily maximum dose of acetaminophen for elderly patients is 3,000 mg (don't blame us … blame the FDA), and the frequency suggested in "E" would far exceed this amount.
When determining what medications are appropriate for treating pain, it helps to know what type of pain the patient has.
Question 27.2.2 Cancer is known to cause which type(s) of pain?
C) Soft tissue/bony pain.
D) Pain from increased intracranial pressure.
E) All of the above are types of pain.
Answer 27.2.2 The correct answer is "E." Physiologic pain is separated into four categories: soft tissue or bony pain (also called somatic pain), neuropathic pain, visceral pain, and the pain of increased intracranial pressure. An example of somatic pain is the musculoskeletal pain (e.g., sports injuries and fractures) that everyone experiences at some point. Neuropathic pain is generally described as burning and results from nerve damage, inflammation, or compression. Visceral pain comes from distention of an organ capsule (e.g., liver enlargement from metastases, and colicky pain from the colon). Depending on where a metastasis or primary tumor is located, it may cause somatic pain (e.g., bone tumors), neuropathic pain (e.g., Pancoast tumor), visceral pain (e.g., peritoneal carcinomatosis), or a headache from increased intracranial pressure.
Avoid using meperidine (Demerol). It has toxic metabolites that may cause agitation and seizures. Meperidine can also interact with a number of drugs to cause serotonin syndrome.
You decide to increase her morphine dose.
Question 27.2.3 Which of the following statements is TRUE?
A) Intravenous morphine is 10 times more potent than oral morphine.
B) Naloxone should be given if a hospice patient near death demonstrates confusion, decreased responsiveness, a slowed respiratory rate or cool extremities.
C) Patients exhibiting a local rash or intense pruritus at the site of intravenous morphine administration must be considered allergic and given an alternate opiate.
D) Tolerance to morphine does not occur in patients with cancer, so any increased analgesic need is due solely to uncontrolled pain.
E) Renal and hepatic insufficiency both contribute to the accumulation of morphine and its metabolites.
Answer 27.2.3 The correct answer is "E." "A" is incorrect. Intravenous (IV) morphine is about three times as potent as oral morphine. "B" is incorrect. Patients who are within several days or hours of death often exhibit pallor, peripheral vasoconstriction, apneic episodes, and obtundation as part of the physiologic process of dying. Counseling the family and patient is preferable to administering naloxone, which can cause abrupt opiate withdrawal and significant distress and discomfort to the patient (again, don't make her ghost haunt you). "C" is also incorrect. Local histamine release is a known effect of IV morphine administration. Histamine-mediated skin changes proximal to the IV infusion site of morphine do not represent a contraindication to future morphine use. In fact, antihistamines (e.g., diphenhydramine) can be used to counter morphine-related histamine effects, such as rash, itching, and hypotension. But again, if you choose to use an antihistamine you need to monitor for delirium. "D" is incorrect. All patients can develop tolerance to the effects of morphine. Of course, in patients with terminal cancer, increasing opiate requirements are often entirely due to increasing pain. And even if your dying patient develops morphine tolerance, you still need to treat the pain. Finally, "E" is correct. Patients with renal and hepatic insufficiency can accumulate metabolites of morphine, some of which are helpful in pain control and others of which may have an anti-analgesic effect. These patients often need lower doses of opiates. If a patient is actively dying and has evidence of renal failure, opioid doses can often be decreased significantly without a worsening of pain control. Fentanyl and methadone are considered the safest opiates in renal failure although methadone use is complicated by the long half-life.
Start patients on a regimen to prevent constipation when initiating opioids. Think about the bowel regimen each time you increase the opiate dose. It will save you and your patient a lot of grief in the long run.
For patients whose pain cannot be controlled with typical treatments, lidocaine infusions have been shown to be beneficial.
Question 27.2.4 Which of the following statements is NOT accurate regarding the appropriate use of opiates in end-of-life situations?
A) At times, delirium can be improved with opiate dosage reduction and/or the addition of opioid-sparing analgesics (e.g., acetaminophen).
B) If oral morphine cannot be swallowed, then either an enteral feeding tube or a parenteral route (IM/IV/subcutaneous) must be used.
C) Dosage conversion from one opiate to another is affected by the type of opiate used and the route of administration.
D) Transdermal opiate delivery products are expensive, have a slow onset of action, and have erratic absorption.
E) There is no pre-established ceiling dosage for opiates, and you may increase the opiate dose until adverse side effects occur.
Answer 27.2.4 The correct answer (and the false statement) is "B." Concentrated oral morphine solutions (20 mg/mL) can be given in small amounts to patients who are unable to swallow. While it was previously thought that morphine elixir worked by absorption through the buccal mucosa, it is now believed to trickle down the throat to be absorbed through the gastric mucosa. Fentanyl is the only opiate absorbed via the buccal mucosa (thus, the fentanyl lollipops). A secret that drug companies do not want you to know is that you can avoid the expense of fentanyl lollipops by using fentanyl IV solution orally for control of breakthrough pain. Since concentrated morphine elixir is effective in patients who cannot swallow, feeding tubes or parenteral routes of administration are unnecessary. "A" is true. Delirium is a common and disturbing finding toward the end of life, and it is sometimes precipitated or exaggerated by opiates. On the flip side, untreated pain can cause delirium, and the delirium may improve when opioid doses are escalated. In these situations, it can be helpful to rotate opiates because the lack of cross-tolerance means that the dose can often be decreased while maintaining the same level of pain control. Acetaminophen is the safest opiate-sparing analgesic, and its adjuvant action may allow for opioid dosage reduction without a loss of overall analgesia. In the appropriate patient, NSAIDs may also be used.
"C" is true. When a patient chronically taking one opiate switches to another, a dose adjustment calculation must be made. You cannot switch milligram for milligram. Also, some authorities recommend that after the calculation, you slightly reduce the dose of the new opiate due to incomplete cross-tolerance (refer to opioid dose conversion charts available in numerous pharmaceutical texts and handbooks). "D" is true. The transdermal fentanyl patches, though convenient, have fluctuating bioavailability over the three days that each patch is worn, and breakthrough doses of an alternative opiate should be available. Fentanyl is also fat-soluble and absorption/bioavailability is decreased in thin and/or cachectic patients. The fentanyl patches are expensive and initially have a slow onset until a steady state is achieved. For this reason, a fentanyl patch should never be used alone as an initial treatment of acute pain. In fact, if you want to avoid a lawsuit, a fentanyl patch should never be used as the first method to treat pain in an "opiate-naïve" patient. "E" is true. Because of the extraordinarily wide dosage range of opiates, the ceiling dosage cannot be calculated or assumed. Rather, analgesic requirements allow for continual increase unless adverse side effects clearly undermine the use of the drug.
There is no consistent relationship between blood levels of morphine and analgesic effects. This is because of tolerance, individual variability in drug effect, etc. Thus, there is no single "right" dose. You should titrate morphine to the desired effect while watching for side effects.
You increase the morphine dose considerably over a 2-week period and your patient begins having escalating pain and muscle twitching.
Question 27.2.5 Which statement is true about opioid-induced hyperalgesia (OIH)?
A) Patients with OIH always become delirious.
B) When a patient has OIH, the pain does not improve when the opioid dose is increased.
C) The pain in OIH is described as a worsening of the original pain being treated.
D) OIH needs to be differentiated from worsening underlying disease.
Answer 27.2.5 The correct answer is "D." Before we presume that a patient has OIH, we need to ensure that the increase in pain is not due to further disease progression. We also need to consider increased pain resulting from increased activity or other exacerbation (such as trips to x-ray or radiation therapy). Additional features that can help distinguish OIH from increased pain include: the development of muscle twitching, presence of allodynia (pain elicited from ordinarily nonpainful stimuli, such as stroking skin with cotton—although this can occur with neuropathic pain syndromes as well), and development of seizures or delirium. However, not all patients with OIH become delirious, making "A" incorrect. The key feature of OIH is that the pain increases as the dose of the opiate is increased and will decrease when the dose is decreased. We are not certain why OIH occurs but several mechanisms have been proposed. One proposed mechanism is upregulation of NMDA receptors from chronic use of high-dose opiates, which is why switching to an opiate with NMDA antagonism could prove helpful (such as methadone or ketamine). However, OIH can still occur in patients new to opiates and on low doses, so there is still more research needed on this subject. "C" is incorrect as well. OIH typically produces diffuse pain, less defined in quality and extending beyond the pre-existing pain distribution.
You are concerned about OIH and you decide to rotate to methadone.
Question 27.2.6 Which of the following statements is FALSE regarding the use of methadone?
A) Methadone can be legally prescribed for pain and addiction by a physician with a current schedule II DEA license.
B) Methadone is more easily absorbed by those with bowel problems than is sustained-release morphine.
C) The half-life of methadone is 22 hours.
D) Methadone may be useful for neuropathic pain because it inhibits receptors in the dorsal horn of the spine.
E) Methadone is primarily excreted in the stool and thus drug dosages do not need to be modified in those with mild to moderate renal disease.
Answer 27.2.6 The correct answer (and false statement) is "A." Methadone can be prescribed for pain control by physicians with a schedule II DEA license but cannot be prescribed for addiction or opiate withdrawal without a special license. "B" and "C" are true. Methadone has a long half-life, and sustained-release preparations are not needed. Sustained-release morphine may pass unabsorbed in patients with short gut or dysfunctional gut, whereas methadone would be absorbed. "D" is true; methadone may be especially useful in treating neuropathic pain. "E" is also true. Methadone is primarily excreted into the GI tract. Patients with liver disease should have doses adjusted. However, those with renal disease may tolerate "normal" doses since renal excretion is a minor part of methadone elimination.
When it comes to switching or dosing opiates there are several useful tips that we like to use: (1) don't forget to account for incomplete cross-tolerance when switching classes of opiates—reduce the dose of the new opiate by 30% to 50%; (2) when opiates are not helping, increase the dose by 50%; essentially, treat opiates like you would treat a loop diuretic—if 60 mg of IV furosemide does not work, you wouldn't try 61 mg (or at least we hope not!), but rather go to 90 or 120 mg; (3) for an opiate-naive patient who is starting a patient-controlled analgesia (PCA) pump, go with morphine 2 mg IV Q10 minutes as needed without a continuous ("basal") infusion.
Since methadone interacts at the NMDA receptors, it is the opiate of choice for neuropathic pain, which is often poorly responsive to other opiates. In addition, methadone is the only long-acting opiate that comes in a liquid form and can be given buccally or in an enteral tube. Methadone can be dosed every 8 to 12 hours with many pain patients requiring Q8 hour dosing. Remember that methadone prolongs the QT in high doses and can cause torsades de pointes.
Your nurse calls you about your patient and reports that her pain level has been rising, and despite significant increases in both basal and breakthrough opiate therapy, the patient's pain is uncontrolled. The nurse asks you if there is something else that can be added to the opiates as an adjunctive treatment for pain. For no explicable reason, you cannot get gabapentin out of your head—even though you know it's probably useless for this patient.
Question 27.2.7 Which of the following is TRUE regarding the use of the gabapentin?
A) Gabapentin is hepatically cleared and dose adjustment is needed in patients with liver disease.
B) The primary utility of gabapentin is in neuropathic pain.
C) Gabapentin primarily works via the μ-opiate receptors.
D) The most common side effects of gabapentin are supraventricular arrhythmias (thus limiting its utility in heart failure patients).
E) If a patient does not respond to gabapentin, she will also not respond to pregabalin.
Answer 27.2.7 The correct answer is "B." Gabapentin has proven to be a marginally effective (NNT = 7) therapy for a number of diseases that manifest with neuropathic pain, including postherpetic neuralgia, diabetic neuropathy, and cancer-related neuropathic pain. "A" is incorrect because gabapentin is excreted unchanged through the kidneys—a plus for patients with working kidneys on multiple drugs. Why do we like drugs that are not hepatically cleared? They do not interact in any of the cytochrome P450 pathways and therefore have few drug–drug interactions. "C" is incorrect. The mechanism of gabapentin is complex and not fully understood, but we are fairly certain that it does not work through the μ-opiate receptors. The literature suggests there is an intricate interplay with multiple receptors, including voltage-dependent calcium channels and increasing synthesis of GABA (more than you wanted to know, right?). "D" is incorrect. The most common side effect of gabapentin is its effect on cognition, causing dizziness and somnolence. Gabapentin can also cause edema, which can be problematic for patients with heart failure. "E" is incorrect. Although gabapentin and pregabalin are thought to have the same mechanism of action, it appears that patients that some patients will respond to one but not the other. Another important distinction between gabapentin and pregabalin is the time needed to titrate to an effective dose. With gabapentin we typically start at 100 to 300 mg and escalate the dose over the course of weeks up to 3,600 mg divided three times a day; alternatively, pregabalin starts at 75 mg daily and reaches a max dose of 300 mg BID within a week of initiation.
An opiate-naive patient should never be started on a fentanyl patch. A patient needs to be taking an oral morphine equivalent of at least 25 mg in 24 hours before the lowest dose (12.5 mcg) fentanyl patch can be applied.
As time goes on, the patient has other concerns, including constipation, weight loss of 20 pounds over 2 months, sleeplessness, nausea, and anxiety. In addition, she expresses how her loss of functional abilities is a hardship for her and her adult daughter who serves as her primary caregiver. Her guilt for losing her health is a continual source of frustration and anger.
Question 27.2.8 What is true regarding her social and emotional pain?
A) It will not affect the patient's analgesic requirements.
B) It will likely complicate treatment adherence.
C) Active treatment of emotional sources of pain should only occur after the physical source has been addressed and treated.
D) Prophylactic antidepressants in patients within 6 months of death decrease the probability of developing depression.
Answer 27.2.8 The correct answer is "B." Adherence, always an issue, is especially compromised in those dying patients whose social, spiritual, and emotional problems are not effectively addressed. Similarly, analgesic control of somatic pain is complicated when social, emotional, and spiritual sources of pain exacerbate the patient's response and perception to somatic pain. Concurrent treatment of all sources of pain is necessary. Antidepressant therapy in dying patients who do not have clinical depression offers no prophylaxis against the development of depression.
You estimate your patient's life expectancy to be 2 months or less. Her frailty has progressed to the point where she is bedbound and utterly dependent for all of her ADLs. You have made some adjustments, and she is now on stable doses of the following medications:
You want to optimize her medications.
Question 27.2.9 Which of the following is the most appropriate medication adjustment to make at this time?
A) Hydromorphone → scheduled controlled release morphine.
B) Hydromorphone → scheduled immediate release morphine.
C) Hydromorphone → scheduled controlled release morphine and immediate release morphine as needed.
D) Acetaminophen → immediate release morphine.
Answer 27.2.9 The correct answer is "C." A patient who has reached a stable dose of short-acting opiate, such as hydromorphone, should subsequently be switched to a long-acting opioid agent. An immediate release medication should be available for acute "breakthrough" pain. There is no reason to change the acetaminophen. Nortriptyline is sometimes useful as an adjuvant medication and is particularly helpful when treating neuropathic pain.
The hospice nurse calls you. Your patient is at home and has become restless with slow respirations (6/min) along with paroxysmal coughing and gagging with a large amount of secretions.
Question 27.2.10 The following are all appropriate orders for this patient EXCEPT:
A) Obtain subcutaneous access through placement of a subcutaneous button or butterfly needle.
B) Lorazepam 1 to 2 mg PO or SL every hour PRN.
C) Glycopyrrolate 2 mg PO or SL every 4 hours PRN.
D) Midazolam 0.4 to 4 mg SC every hour PRN.
E) Naloxone 2 mg SC every 2 hours PRN.
Answer 27.2.10 The correct answer is "E." Naloxone is a potent opioid receptor antagonist. Although the sudden change in the patient's status could be partly due to opiate accumulation, the risks of naloxone antagonism are great and include severe pain, cardiac arrhythmias, and seizures (remember, you don't want that ghost haunting you). Withholding or reducing the next dose of opiates is a safer approach. A subcutaneous infusion pump ("A") may allow effective administration of medications and fluids in patients who cannot tolerate oral administration. The use of hydration at the end of life is controversial. Withholding fluids and nutrition has strong merit, but the evidence is not compelling enough to declare that fluid infusion is futile and possibly harmful in this setting. In addition, dehydration is a common cause of delirium at the end of life, and her confusion may improve with gentle hydration. It is more important to review the patient's goals and only administer fluids if consistent with her goals. Glycopyrrolate ("C") has been shown to decrease oral/pulmonary secretions that lead to the "death rattle" in the final days and hours of life. Such treatment benefits the patient and her grieving family and friends. "B" and "D" may also be useful. Benzodiazepines have the potential to reduce anxiety, agitation, and insomnia; however, any benzodiazepine can worsen confusion and cause delirium. Benzodiazepines with an extended half-life (e.g., diazepam and chlordiazepoxide) should generally be avoided because of the potential for toxic accumulation.
Objectives: Did you learn to…
Define major physiologic pain categories?
Describe the pharmacology of pain control?
Prescribe opiate pain medications and adjuvant therapies for pain?
Identify emotional, social, and spiritual symptoms and recognize how they can affect pain management?