Managing an Acute Pain Crisis
in a Patient With Advanced Cancer
“This Is as Much of a Crisis as a Code”
The assessment and management of an acute pain crisis in
the setting of advanced illness is challenging. Using the
case of Mr X, a 33-year-old man with advanced metastatic
mucinous adenocarcinoma of the appendix and “15 out of

10” pain, we explore the issues of acute pain and its man-
Mr X is a 33-year-old man with a 4-year history of meta- agement. We define a pain crisis as an event in which the
static mucinous adenocarcinoma of the appendix. Over thecourse of his illness, Mr X completed several cycles of che- patient reports pain that is severe, uncontrolled, and caus-
motherapy and had several percutaneous draining osto- ing distress for the patient, family members, or both. Our
mies for small-bowel obstruction due to peritoneal carci- management strategy focuses on making a pain diagno-
nomatosis. His most recent admissions were triggered by sis, differentiating reversible from intractable causes of pain,
protracted nausea and vomiting and recurrent small-bowel and making decisions about further workup; selecting the
obstructions associated with increasing abdominal pain.
opioid and monitoring and treating opioid adverse effects;
In recent months, Mr X’s overall care had been managed titrating and rotating opioid and coanalgesics; consulting
by his medical oncologist and the anesthesia pain service.
In addition, on the admission prior to this, he had been briefly experts to treat a pain crisis as quickly as possible to pre-
seen by a palliative care physician. His wife reported that vent unnecessary suffering; and co-opting the available insti-
he had been “close to death” on several previous admis- tutional resources. The timely intervention of a palliative
sions. Mr X and his family were aware of the extent of his care team and its expertise can provide the staff, patients,
disease but wanted aggressive life-prolonging treatment to and their families the benefit of an interdisciplinary approach
continue, including cardiopulmonary resuscitation. Mr X’s and help the patients address goals of care; understand the
baseline chronic abdominal pain had nociceptive, visceral, benefits and risks of treatment decisions; and meet the psy-
and neuropathic features and had been difficult to manage.
chological, social, and existential needs of the patient and
After a variety of opioid trials, he had finally obtained someanalgesia on escalating doses of intravenous (IV) metha- the family commonly seen in this setting.
done. His methadone dose at home after his last admission was 800 mg over 24 hours (200 mg IV every 6 hours), withhis wife administering each 200-mg dose over a 20- to 30- regimen was contraindicated because of the finding of a QTc minute period. A visiting nurse service and a home care in- prolongation on an electrocardiogram with the conse- fusion company oversaw his methadone administration.
quent potential for an arrhythmia led to the decision to bring One day before his final hospital admission, Mr X under- went a celiac plexus block in an attempt to improve his pain Author Affiliations: Department of Neurology, Pain and Palliative Care Service,
relief and decrease his opioid requirements. Two hours later Memorial Sloan-Kettering Cancer Center, New York, New York.
he developed fever and severe abdominal pain, self-rated as Corresponding Author: Kathleen M. Foley, MD, Weill Medical College of Cornell
University, and Department of Neurology, Pain and Palliative Care Service, Me-
“15 out of 10” on a 0-to-10 scale. The patient’s unrelieved morial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021 (foleyk pain and the visiting nurse’s concern that the methadone
Perspectives on Care at the Close of Life is produced and edited at the University
of California, San Francisco, by Stephen J. McPhee, MD, Michael W. Rabow, MD,
CME available online at
and Steven Z. Pantilat, MD; Amy J. Markowitz, JD, is managing editor.
and questions on p 1487.
Perspectives on Care at the Close of Life Section Editor: Margaret A. Winker, MD,
Deputy Editor.
2008 American Medical Association. All rights reserved.
(Reprinted with Corrections) JAMA, March 26, 2008—Vol 299, No. 12 1457
PERSPECTIVES ON CARE AT THE CLOSE OF LIFE Upon his arrival at the hospital, the patient’s tempera- Mr X and his family, as homelike as possible, in which all ture was 40.0°C, his blood pressure was 98/40 mm Hg, his of the monitoring necessary to manage his pain and other heart rate was 116/min, and his respiratory rate was 34/ symptoms was available. As he became more comfortable, min. When examined by Dr P, the attending physician on his methadone dose was stabilized, and Mr X made tele- the medicine team, he was sitting up in bed in acute dis- phone calls to say good-bye to family and friends.
tress. He was cachectic and jaundiced and complained of Over the ensuing hours, his pain again started to esca- severe abdominal pain. His abdominal examination re- late and the doses of IV methadone were titrated up. Even- vealed diffuse tenderness to palpation with rebound and tually, he became sedated without evidence of distress, but guarding. There was pus draining through the skin sites of he developed myoclonic jerks. He was given a 60-mg dose previous percutaneous draining ostomies.
of dantrolene intravenously and the myoclonus resolved.
The initial impression was that Mr X was in an acute pain Approximately 36 hours after admission, Mr X died peace- crisis superimposed on chronic abdominal pain. The pain fully. His wife, their 2 dogs, and several family members and exacerbation was thought to be associated with acute peri- tonitis or bowel perforation due to the progressive meta- Dr P and Dr S were interviewed by a Perspectives editor static disease or the recent celiac plexus block. The main priority of the medical team was pain crisis management andreestablishing the goals of care in the setting of the rapid PERSPECTIVES
worsening of the patient’s condition. Despite the severity DR P: I think as a primary medical team, we were becoming of his pain, Mr X was alert and oriented with clear capacity uncomfortable with the dosage and the amount of pain medi- to engage in decision making about his care.
cation the patient was requiring . . .
The medical team, in consultation with the anesthesia pain DR S: The patient looked ashen and stressed. He was just service, decided to transfer Mr X to the intensive care unit holding his belly and he looked incredibly uncomfortable. He (ICU) because of plans to control his pain with high-dose was sweating and basically telling us that he really, really IV opioids and ketamine. This would require a level of ob- wanted us to do whatever it took to get his pain under control. servation and monitoring not available on a medical ward.
Mr X’s electrocardiogram again showed a prolonged QTc Assessment and Management of an Acute Pain Crisis
interval. Because of the possibility that this was associated The assessment and management of an acute pain crisis in with the high dose of parenteral methadone, the decision the setting of advanced illness are challenging.1,2 Using Mr was made to discontinue the methadone and rotate to IV X’s case, we outline a management strategy that focuses on hydromorphone. Hydromorphone infusion was titrated from (1) making a pain diagnosis, differentiating reversible from 30 mg/h to 80 mg/h with IV boluses of 80 mg every 10 min- intractable causes of pain and making decisions about fur- utes over the early morning hours without any improve- ther workup, (2) selecting the opioid and monitoring and ment in his pain. He was also given a racemic ketamine in- treating adverse opioid effects, (3) titrating and rotating opi- fusion titrated up to 7 mg/h. After almost 5 g of oids and coanalgesics, (4) consulting experts to treat a pain hydromorphone in a 10- to 12-hour period, the patient re- crisis as quickly as possible to prevent unnecessary suffer- ing, and (5) identifying and co-opting the available institu- Dr S, the palliative care consultant, met with the family and discussed the risks of restarting IV methadone despiteQTc interval prolongation. Mr X and his wife acknowl- Definition of a Pain Crisis
edged that he was dying, requested use of any medications We define a pain crisis as an event in which the patient re- necessary to stop his pain, and declined further life- ports severe, uncontrolled pain that is causing the patient, prolonging measures such as cardiopulmonary resuscita- family, or both severe distress. The pain may be acute in on- tion. Pain relief, other symptom control, and facilitating the set or may have progressed gradually to an intolerable thresh- opportunity for him to say good-bye to family and friends old (as determined by the patient), but requires immediate became the focus of his care. The immediate goal was to man- intervention. National Comprehensive Cancer Network pain age the acute pain crisis as quickly as possible. The hydro- management guidelines identify a pain emergency as an event morphone was discontinued and the methadone was re- in which patients have severe pain (a numerical estimate of started with IV boluses of 40 mg every 15 minutes until pain at least 7 on a 10-point scale) that requires rapid opioid ti- relief was obtained. It had taken almost 12 hours to reduce tration to provide analgesia.3 There are no epidemiological his pain from 15 to 2 on a scale of 0 to 10. Within several data to suggest how commonly pain crises occur. Our own hours, a total dose of 1.59 g of methadone was adminis- experience at Memorial Sloan-Kettering Cancer Center sug- tered, and Mr X reported minimal and adequately con- gests that of about 120 inpatient consultations a month, our trolled pain of 2 on a 0-to-10 scale. His mental status re- Pain and Palliative Care Service is called for what is iden- mained intact. His wife stayed with him throughout. During tified as a pain crisis by the referring physician as fre- this period, the ICU staff created a private environment for quently as 20 to 30 times a month—the message usually con- 1458 JAMA, March 26, 2008—Vol 299, No. 12 (Reprinted with Corrections)
2008 American Medical Association. All rights reserved.
PERSPECTIVES ON CARE AT THE CLOSE OF LIFE veyed is that the patient needs to be seen “right now.” Thetreatment plan starts with a rapid clinical assessment, titra- Box 1. Assessment of a Pain Crisis in a Patient
tion of analgesics, and direct supervision by a physician/ With Advanced Cancera
nurse team. When the medications or doses are not famil- Believe the patient’s complaint of pain.
iar to the clinician providing direct patient care, appropriate Take a careful history of each pain complaint and place it experts and resources should be consulted to help outline temporally in the patient’s cancer history (extent of dis- a plan of care; guide medication titration; monitor the out- ease, recent treatments, and interventions).
comes; and provide support to staff, patient, and family.3-5 Assess the characteristics of each pain, including its site, itspattern of referral, and its aggravating and relieving fac- Pain Assessment During a Pain Crisis
DR S (THE PALLIATIVE CARE CONSULTANT): The first thing was Clarify the temporal aspects of the pain (acute, subacute, to understand what happened. Why was he saying that his pain chronic, episodic, intermittent, breakthrough, or incident).
was worse than it had ever been before? . . . I explained to them Clarify the response to previous and current analgesic thera- [patient and family] that something potentially catastrophic had happened since the celiac plexus block, and it might be aperforation. He very well might be dying of that, and then there Evaluate the psychological state of the patient (eg, de-lirium, terminal agitation, existential crisis; all can contrib- was the severe pain we had to deal with. A thorough assessment of a pain crisis is just like the evalu- ation of any other medical emergency. The basic pain as- Ask whether the patient has a past history of alcohol or drugdependence (may influence the degree of opioid requirements).
sessment principles are outlined in BOX 1.6 Pain intensity,
pain relief, and adverse effects of the therapy should be moni-
Perform a careful medical and neurological examination.
tored and recorded until the resolution of the pain crisis.
Define the goals of the pain intervention and be aware of Based on Mr X’s description of severe abdominal pain and the associated fever, which started approximately 2 hours Order and personally review any appropriate diagnostic pro- after receiving a celiac plexus block, bacterial peritonitis cedures (diagnostic tests and interventions are dependent caused by perforation of an underlying malignant bowel ob- struction was considered to be a likely contributing cause Treat the patient’s pain at the same time as determining the of his pain crisis. High fever and hypotension due to bac- terial peritonitis can be a terminal event in a patient with Provide continuous monitoring and support of the patient and family until the pain is brought under control.
In assessing both the pain experience and patients’ desired Continuously reassess the patient’s response to pain therapy.
goals of care, clinicians should use a communication ap- Continuously document drug doses administered, patient proach that allows patients to lead the discussion, beginning response, and reasons for dose escalation.
with their understanding of the nature of the pain, its mean- Talk to the dying patient’s family about what to expect dur- ing to them, and how they prioritize its management in es- ing the dying process and availability of social work and chap- tablishing treatment goals.7,8 Patients can often distinguish pain from their experience of suffering, which frequently stems from their multiple concerns about being a burden to their loved ones, fear of dying, and concerns about their family.9 Anxi-ety, depression, existential distress, and delirium are com-mon psychological symptoms that can occur in a patient withsevere cancer pain and need to be addressed.10 and pain descriptors and takes only 15 seconds to com- To assess Mr X’s pain, it was essential to establish a clear plete, allowing for frequent repeated use.16 Studies using the description of its onset, localization, pattern of referral, ex- MPAC have demonstrated that the perception of pain in- acerbating and relieving factors, and relationship to the re- tensity contributes significantly to subjective distress, but cent procedure and changes to his analgesic regimen (Box 1).6 the perception of inadequate pain relief was the more im- Pain and symptom assessment tools that could be used to portant factor. In Mr X’s case, a numeric scale provided a define and quantify pain include the Brief Pain Inven- useful outcome measure for the treating team, who ob- tory,11 the McGill Pain Questionnaire,12 the Visual Analog served the correlation of the scale representing decreased Scale for the Management of Acute Pain,13 the Edmonton pain with the patient’s appearance of improved comfort and Symptom Assessment Scale,14 the Memorial Symptom As- sessment Scale,15 and the Memorial Pain Assessment Card This patient’s pain was thought to be mixed nociceptive, (MPAC).16 Of these, the MPAC (FIGURE) provides a vali-
visceral, and neuropathic with inflammatory components.
dated method for rapid assessment of the patient; evalua- This pain diagnosis was based on his previous pain history, tion of the patient’s pain intensity; and degree of relief, mood, his radiological studies consistent with malignant bowel ob- 2008 American Medical Association. All rights reserved.
(Reprinted with Corrections) JAMA, March 26, 2008—Vol 299, No. 12 1459
PERSPECTIVES ON CARE AT THE CLOSE OF LIFE struction, his ascites, his multiple draining infected osto- documentation should specify the plan and rationale for the mies, and the high likelihood of perineural tumor infiltra- workup, congruent with the goals of care and options con- tion. These pain mechanisms can be inferred from animal sidered. This is particularly important if a decision regard- and human studies of malignant bowel obstruction and tu- ing further workup and or management is focused on pro- viding the patient with comfort.7 In a patient close to death,no further diagnostic studies should be ordered and “rou- Diagnostic Studies and Treatment Strategy
tine” orders should be rewritten to focus on patient comfort.
Mr X presented as a medical emergency with severe intol- Congruent to the goals of care, rapid titration of the an- erable pain as his major symptom. Rapid assessment of his algesias with close monitoring of the patient for pain and medical status was necessary to establish a correct diagno- adverse effects is paramount. The main principles of opi- sis and develop a treatment plan. Although this patient re- oid selection are outlined in BOX 2. Opioids should be ti-
fused further diagnostic studies, a flat plate of the abdo- trated aggressively (BOX 3, TABLE 1, and TABLE 2). Nono-
men to assess for free air and bowel dilatation or a computed pioids such as IV ketorolac or corticosteroids to address the tomography scan to confirm bowel perforation to assess the inflammatory components of pain may be combined with severity of bowel obstruction may be appropriate diagnos- opioids (TABLE 3).34-36 Spinal analgesia may be advanta-
tic studies in this situation.19 Broad-spectrum antibiotics were geous because of the lower opioid dose needed, along with a reasonable treatment option for one aspect of his pain ex- the possibility of using a local anesthetic.
acerbation. The extent of the diagnostic workup to be done In Mr X’s case, the medical team in consultation with an- depends on the clinical situation (reversible crisis vs antici- esthesia and palliative care services developed a treatment pated worsening of a progressive disease that led to the cri- strategy that reflected an end-of-life care pathway address- sis), the goals of care, the patient’s wishes, and the risk- ing the patient’s physical, psychological, social, and spiri- benefit burden ratio of any diagnostic test considered. Clear tual needs with the needs of his family.37,38 Figure. Memorial Pain Assessment Card
Memorial Pain Assessment Card
4 Mood Scale
2 Pain Description Scale
Put a mark on the line to show your mood.
Circle the word that describes your pain.
1 Pain Scale
3 Relief Scale
Put a mark on the line to show how much pain there is.
Put a mark on the line to show how much relief you get.
Each numbered item is on a card and each card is presented to the patient separately in the numbered order: (1) visual analog scale for pain intensity, (2) modifiedTursky Pain descriptors scale, (3) visual analog scale for pain relief, and (4) visual analog scale for mood.
1460 JAMA, March 26, 2008—Vol 299, No. 12 (Reprinted with Corrections)
2008 American Medical Association. All rights reserved.
PERSPECTIVES ON CARE AT THE CLOSE OF LIFE The Importance of Rapid Pain Control
DR S: I feel that this is as much of a crisis as a code, and we
Box 2. Principles of Opioid Selection
have to be there by the bedside, supporting the primary team. for the Management of Pain
A rapid response to a pain crisis is essential for patients Select the opioid drug based on the patient’s analgesic his- both with early stage disease and those at the end of life.
tory, severity of the pain, and inferred pain mechanism(s).
Failure to adequately manage a pain crisis early in the dis- Take into consideration the patient’s age, metabolic state, ease course encumbers both the patient and family with the presence of major organ failure (renal, hepatic, lung), and fear that escalating pain and lack of effective treatment will Consider pharmacologic issues (eg, potential accumula- In cases of intractable pain refractory to rapid and expert tion of active metabolites, effects of concurrent drugs, and interventions such as opioid escalation or rotation, use of coanalgesics, and anesthetic approaches, clinicians can con- Know the drug class (eg, agonist, agonist/antagonist), sider sedation as a temporary measure while other pain re- duration of analgesic effects, and pharmacokinetic prop- lief measures are being explored. It is helpful to ask the pa- tient (with the family present) if it is acceptable to be sedated Consider which of the available routes of administration for if that is the only way to achieve adequate pain control. For the opioid selected (eg, oral, rectal, transdermal, transmu- some patients, sedation may be the treatment of choice. The cosal, buccal, subcutaneous, intravenous, epidural, intra- use of sedation in the imminently dying has been previ- If nonparenteral administration is chosen, consider whichamong the various drug formulations available for the opi- Use of Opioid Analgesics for a Pain Crisis
oid selected (eg, immediate release, controlled release, liq- in an Inpatient Setting
uid, transmucosal, buccal) is most appropriate.
DR S: I was giving her [Mrs X] that bad news and also explain-ing that if we gave him the pain medication he needed, he wouldprobably go into a deep sleep and not wake up. Principles of Opioid Selection. In a patient who has not
be used with caution and consultation with a palliative care been exposed to opioids in the past (opioid naı¨ve), mor- or pain consultation team is recommended.
phine is generally considered the standard starting drug of Opioid Route. Table 1 provides equianalgesic guidelines
choice (Box 2).41,42 Morphine should be avoided or used with for commonly used opioid drugs to be converted from the caution in patients with renal disease and hepatic insuffi- oral or transdermal route of administration to IV or from ciency. Morphine-6-glucoronide, an active metabolite of mor- phine, contributes to analgesia and may worsen adverse ef- Dose Escalation. Once an appropriate opioid has been
fects as it accumulates in patients with renal insufficiency.43,44 selected, the dose should be rapidly titrated until the pa- Morphine-3-glucuronide, a nonactive metabolite, pro- tient has relief of pain or excessive adverse effects develop duces neuroexcitatory effects and the accumulation of both (Box 3). Based on the pharmacokinetics of the specific opi- of these metabolites is associated with confusion, sedation, oids and current best practice identified in both the Na- and myoclonus.45 For patients with hepatic or renal insuf- tional Comprehensive Cancer Network Cancer Pain Guide- ficiency, an opioid with a short half-life such as hydromor- lines3 and the American Pain Society Guidelines,4 parenteral phone or fentanyl are appropriate choices.
opioids are usually administered to the patient every 15 min- Methadone has been found to provide effective analge- utes as needed. This time interval is based on the approxi- sia for patients whose pain is uncontrolled with other opi- mate time to analgesic effect with IV opioid administration.
oids.46-49 In using methadone, the clinician must be aware To achieve adequate analgesia in opioid-tolerant pa- that the half-life of the drug is highly variable, ranging from tients, it is recommended that the IV dose be incrementally 17 to 50 hours up to 190 hours in some patients with can- increased by 50% (Box 3). Because the analgesic effect is a cer.46,48 More importantly, if switching to methadone, the logarithmic function of the dose of the opioid, a doubling equianalgesic ratio dose depends on the patient’s degree of of the dose in an opioid-tolerant patient may be needed.
tolerance to the previous opioid and can also vary over 10- Opioid Rotation. For patients unable to tolerate escala-
fold (see Table 2).25-28 The significant reduction in opioid tion of their current opioid dose because of adverse effects, doses when switching is thought also to be related, in part, an alternate opioid should be considered (opioid rotation; to d-methadone being a noncompetitive antagonist at the Box 3). Studies involving patients with cancer demon- N-methyl D-aspartate (NMDA) receptor.49 The NMDA re- strate wide interindividual variations in analgesic response ceptor antagonists are analgesic in neuropathic pain and have and adverse effects, and thus it may require a trial of 2 or 3 been shown to block the development of opioid toler- opioid drugs to obtain effective analgesia with tolerable ad- ance.49 In addition, methadone inhibits the uptake of sero- verse effects.51 Tolerance to one opioid does not necessarily tonin and norepinephrine.50 Therefore, methadone should lead to complete tolerance to another (Table 2).25-28 This phe- 2008 American Medical Association. All rights reserved.
(Reprinted with Corrections) JAMA, March 26, 2008—Vol 299, No. 12 1461
PERSPECTIVES ON CARE AT THE CLOSE OF LIFE Box 3. Managing a Pain Crisis With Parenteral Opioids in Patients Currently Receiving Opioid Therapy
Group 1. Patients Who Have Inadequate Pain Relief and No Significant Opioid Adverse Effects
Continue the current opioid and use rescue doses for titration.
If taking an oral opioid, convert the patient’s rescue dose to an intravenous equivalent using relative potency tables (Table 1 andTable 2).
Administer double the rescue dose intravenously.
Repeat same dose in 15 minutes if there is no or minimal pain relief.
If pain persists at 7 or higher on a 10-point scale without adverse effects, increase the intravenous rescue dose by 50%.
Continue to administer this dose every 15 minutes until patient experiences more than 50% pain relief or adverse effects develop.
Consider intravenous adjuvants or coanalgesics (eg, a nonsteroidal anti-inflammatory drug or corticosteroids).
Once the patient has obtained adequate pain relief, calculate the new 24-hour opioid requirements including rescue doses andorder accordingly.
Decide route of opioid administration (eg, oral, intravenous, transdermal) best suited to the patient’s ongoing analgesic needsand adjust dose accordingly.
Group 2. Patients Who Have Significant Opioid Adverse Effects
Discontinue the current opioid and rotate the patient to a different opioid (opioid rotation).
Refer to the equianalgesic tables (Table 1 and Table 2).
If the pain control is good but significant adverse effects are present, reduce the equianalgesic dose (Table 3) of the new opioidby 25% to 50% (accommodates for cross-tolerance); continue to monitor the patient for reduction in adverse effects and ad-equacy of pain relief; and provide for rescue doses for breakthrough pain.
If pain control is poor and significant adverse effects are present, rotate opioids without reduction in the equianalgesic dose;continue to monitor the patient for reduction in adverse effects and adequacy of pain relief; and provide for rescue doses.
For opioid-tolerant patients, estimate the safe starting dose of the new opioid depending on the patient’s tolerance (the higherthe previous opioid dose, the greater the level of tolerance; Table 2).
In all situations of opioid rotation, monitor the patient closely for adequacy of pain relief and reduction of adverse effects.
nomena of incomplete cross-tolerance, as evidenced by im- Use of Adjuvant Coanalgesic Medications
proved pain relief or a reduction in adverse effects follow- Adjuvant coanalgesic medications should be considered early ing opioid rotation, is thought to be related, in part, to a range in pain crisis management (Table 3).69 The term adjuvant of interindividual pharmacogenetic factors including ge- is used to describe different drugs and classes of drugs that netic polymorphisms in the morphine gene and in drug may enhance the effects of opioids or nonsteroidal anti-inflammatory drugs.29 Adjuvants exert independent an- When rotating from a short half-life opioid such as hy- algesic activity in certain circumstances or counteract the dromorphone or fentanyl to another opioid, calculate the adverse effects of analgesics.3,5 Introducing adjuvant coan- equianalgesic dose and estimate the safe starting dose (Table 1 algesic agents concurrently with opioid titration is recom- and Table 2).20-25,27,55 In patients who have adequate anal- mended based on the inferred mechanism of the pain crisis gesia on their current opioid dose but intolerable or un- and their known effectiveness in these situations. Table 3 manageable adverse effects, reduce the calculated equian- lists some of the adjuvant coanalgesic medications that can algesic dose by 25% to 50% or up to 90% in case of methadone be administered through an IV when managing a pain Opioid Adverse Effects. Nausea and vomiting, seda-
For Mr X, the anesthesia pain service recommended ket- tion, delirium, respiratory depression, constipation, multi- amine based on its reported efficacy in neuropathic and can- focal myoclonus, and seizures are known adverse effects of cer pain.30,31 Ketamine, an NMDA antagonist and an anes- opioid drugs (TABLE 4).1,56,63,68 Tolerance develops to some
thetic that does not interfere with respiratory drive, has been of these adverse effects, although at varying rates. For ex- shown to be a potent analgesic in low doses.71 Multiple case ample, tolerance may develop to nausea and vomiting, res- series and small prospective studies using a double-blind, piratory depression, and sedation but does not develop to placebo-controlled approach suggest that very low-dose ket- constipation. Each adverse effect requires a careful assess- amine may potentiate opioid analgesia and reduce pain.30-32,34 The use of ketamine may not only provide greatly im- 1462 JAMA, March 26, 2008—Vol 299, No. 12 (Reprinted with Corrections)
2008 American Medical Association. All rights reserved.
PERSPECTIVES ON CARE AT THE CLOSE OF LIFE proved pain relief but also allow for significant decreases Table 1. Relative Single-Dose Potencies of Commonly Used Opioid
in the dose of current analgesics and sedatives. Some re- Drugs for Pain and Their Oral-Intravenous Ratiosa ports suggest that it is useful in visceral pain as well as neu- Equianalgesic
Intravenous or
Ketamine should be started at a low dose of 0.02 to 0.05 Intramuscular Dose, mg
mg/kg per hour by continuous IV infusion and rapidly ti- trated upward as needed, escalating the dose by up to 100% every 4 to 6 hours, depending on the pain intensity and ad- verse effect profile. In our experience, this dosing regimen is both safe and well-tolerated. Cognitive adverse effects have occurred infrequently at these doses. Because of the sever- ity of his pain, Mr X eventually received 7 mg/h of IV ket- amine, and because he was in a closely monitored setting, a This table should be used as a guide only and not replace a more in-depth review.4 his dose could have been titrated upward even further in Individual dosing and drug selection depend on each patient’s particular situation andcomprehensive assessment.
an attempt to increase his pain relief, had he desired, to al- b Refer to Table 2 for rotation to methadone for long-term administration.
low for a decrease in his methadone requirements. How-ever, at doses of 10 to 20 mg/h, 30% to 50% of patients arereported to develop drowsiness, nightmares, and halluci- Table 2. Variability in Dose Ratios When Switching Oral Morphine,
Oral Hydromorphone, and Transdermal Fentanyl to Methadonea
nations.72 Due to few published data, a Cochrane review con-cluded that the role of ketamine is not yet established.33 To MorphineMethadone Ratio25
develop evidence-based guidelines for cancer patients, ad- Use of Methadone in Pain Crisis Management
Dr S: I told him that if he wanted us to get the pain under con- trol and if the only way that we could do this was with IV metha- done, then we thought that it did not make sense to follow his QT interval, or get EKGs, and we should just put that aside. He said he completely agreed, and his wife said she also a To change from oral morphine to oral methadone for a patient taking 80 mg/d of morphine orally, the equivalent methadone dose based on this study (4:1 ratio) willbe 20 mg of methadone orally every 24 hours. For a patient taking 800 mg/d oral Prior to this admission, methadone was the only opioid that morphine based on a 12:1 conversion ratio, the equivalent methadone dose will be67 mg/24 h. When changing from transdermal fentanyl to oral methadone the dose was effective in at least partially controlling Mr X’s pain. He ratio is reported to remain the same, independent of the fentanyl dose.
Table 3. Adjuvant Drugs for Parenteral Use in Pain Crisis Managementa
Equianalgesic to morphine (10 mg IV morphine = 10 mg Substantial GI and renal toxic effects may precipitate Potential for GI bleed, hyperglycemia, psychosis Inform patient/caregiver that sedation is common If sedation is the goal, it can be given as IV infusion but may cause agitation in elderly or delirious patients Administer slowly over 2-3 min; monitor for sedation If sedation is the goal, it can be given as an IV infusionTachyphylaxis is common Opioid-sparing dissociative agent in higher doses Abbreviations: GI, gastrointestinal; IV, intravenous; NSAID, nonsteroidal anti-inflammatory drug.
a Indications are based on clinical experience and are not necessarily supported by trial data or US Food and Drug Administration approval.
2008 American Medical Association. All rights reserved.
(Reprinted with Corrections) JAMA, March 26, 2008—Vol 299, No. 12 1463
PERSPECTIVES ON CARE AT THE CLOSE OF LIFE had received 800 mg of parenteral methadone in the 24-hour tant administration of CYP3A4 inhibitors such as erythro- period prior to his admission to the hospital in a pain crisis.
mycin, dicumarol, and other drugs (which can inhibit the bio- Based on published pain practice guidelines,3,4 a bolus dose transformation of methadone), hypokalemia, hepatic failure, of 80 to 160 mg (10% to 20% of the 24-hour dose) of metha- and administration of other QT-prolonging agents such as done should be repeated every 15 minutes until the patient chlorobutanol, the preservative in parenteral methadone prepa- experiences pain relief or dose-limiting toxicity. Because of rations.80 Clearly, the benefit of methadone in the individual the prolonged QTc interval, Mr X was rotated to parenteral patient needs to be weighed against the potential for risk of hydromorphone and obtained no relief despite using 80 mg arrhythmia. Each of the associated factors that could con- of hydromorphone per IV with boluses of 80 mg every 10 min- tribute to methadone toxicity need to be evaluated in pa- utes. After reestablishing the goals of care and declining life- tients with a history of significant QTc prolongation.
prolonging therapy, methadone was restarted and titrated up In Mr X, electrolyte correction and the use of preservative- to analgesia over the next few hours.
free methadone would have been one approach to consider This clinical predicament raises several questions: to reduce risk and to allow continuation of methadone.75 What is the relationship between parenteral methadone and Despite the potential risk and consequences of torsades de pointes, his goals of care and lack of pain control with other The relationship between methadone and QTc prolonga- agents favored continuation of parenteral methadone.
tion is well described.73-79 Drug-induced long QT syndrome Could the hydromorphone have been titrated up further? is characterized by a prolonged corrected QT interval (QTc) Abrupt discontinuation of methadone has been reported and increased risk of a polymorphic ventricular tachycardia, to cause pain escalation in 12 of 13 patients who were re- also known as torsades de pointes. Published studies sug- ceiving methadone as a third- or fourth-line opioid, de- gest that QT prolongation is context-dependent and occurs spite titration of the alternative opioid to the highest toler- more frequently with high doses of methadone, concomi- ated dose.81 If rotation from high-dose methadone to an Table 4. Opioid-Related Adverse Effects During Rapid Opioid Escalation Management Influenced by Goals of Care1,27,28,51
More Likely to Be Seen in Patients
Adverse Effects
With the Following Conditions
Use benzodiazepinesReduce opioidRotate opioid57,58 Avoid sedating medications, unless essential Rotate to opioid with short half-life and no active metabolites Discontinue all medications that can contribute to the sedation Rotate to opioid with short half-life and no active metabolite Rotate opioid to short half-life drug without active metabolites If no response to naloxone, consider intubation Rotate opioid to another opioid with less histamine release potential64,65 Abbreviation: COPD, chronic obstructive pulmonary disease.
a Naloxone has the potential to increase pain in nearly all cases and should be administered with caution, understanding that only unacceptable and life-threatening opioid-induced sedation and respiratory depression should be reversed by naloxone (respirations Ͻ8/min, shallow respirations, O2 saturation less than 92%, difficult to arouse). If a decision touse naloxone is made, 1 ampule (0.4 mg) needs to be diluted in 9 mL of normal saline and administered slowly, 0.1 to 0.2 mg (1- to 2-mL increments) every 2 to 3 minutes toachieve the desirable level of opioid-agonist respiratory depression reversal and alertness without pain flare. The half-life of naloxone is shorter than for many oral, long-actingopioids, so repeated doses of naloxone may be needed, and careful patient monitoring with continuous pulse oximetry and nasal cannula oxygen are recommended. If therespiratory depressant effects of a long half-life drug such as methadone is required, a naloxone infusion should be used (2 mg/50 mL of dextrose with water or normal saline [0.4mg]. Infuse 0.4 to 0.8 mg/h. Titrate infusion rate to desired effect). For opioid-induced respiratory depression and sedation caused by partial agonists/antagonists, much largerdoses of naloxone may be required. For patients taking buprenorphine, naloxone may be ineffective. If intravenous boluses (typically 0.4-2 mg) are effective, start naloxone dripif on fentanyl patch, methadone, or other long-acting medications/delivery systems. Monitor for pain escalation after administering naloxone.
1464 JAMA, March 26, 2008—Vol 299, No. 12 (Reprinted with Corrections)
2008 American Medical Association. All rights reserved.
PERSPECTIVES ON CARE AT THE CLOSE OF LIFE alternate opioid is necessary, frequent monitoring of the pa- nently dying and distinguishes it from physician-assisted tient for pain escalation, withdrawal symptoms, or overse- dation is essential. A step-wise approach is recommended, The house officer’s intent in rapidly titrating Mr X’s opioid decreasing the methadone dose by one-third daily while add- dose was to reduce his pain and to improve his quality of life, ing the new opioid in equianalgesic doses. This approach albeit recognizing that this approach could potentially has- helps to prevent symptoms of withdrawal from methadone ten the patient’s death.94 Yet 2 studies involving terminally ill as well as adverse effects from rapid up-titration of the al- cancer patients receiving palliative care found no difference ternate opioid. Mr X received almost 5 g of hydromor- in the time to death when comparing patients sedated to con- phone without evidence of analgesia or adverse effects, so trol refractory symptoms with patients who were not se- it could have been further escalated. Practically speaking, dated.86,91 A study of survival following withdrawal of life- using 80-mg boluses of a drug that comes in 2-mg and 10-mg sustaining measures in ICU patients who were dying observed vials is onerous for pharmacists to prepare, and often there that the patients receiving morphine lived longer than those who did not.92 Data from the National Hospice Outcomes How difficult is it to rotate to methadone? Project found opioid dosing to be associated with the time of Any rotation to methadone requires frequent monitoring death but it was only a minor factor in the variation in sur- of the patient for undertreatment, withdrawal symptoms, or vival.93 Despite these data, health care professionals com- oversedation. Methadone is a unique opioid and an increas- monly have concerns about their role in hastening a patient’s ing number of case reports describe improved pain relief af- death.94,95 These concerns can be addressed by institutions in ter rotation to methadone.25-28,82,83 Patients rotated to paren- the form of guidelines or pathways that make transparent the teral methadone may have incomplete cross-tolerance. The indications for opioid titration and symptom outcome end ratio for calculating the safe initial continuous infusion metha- points (eg, evidence of patient comfort) that allow for clear done dose can be much lower than the published single-dose documentation of goals of treatment.
equianalgesic dose ratios (Table 2).25,26,84,85 Methadone, therefore, should be used with caution, and CONCLUSION
consultation with a palliative care or pain consultation team DR P: The day after he [Mr X] passed away, the resident, the medical student, the interns, and I got together, and we spentalmost an hour debriefing about the experience. It was an ex- Pain Crisis Management and Institutional Resources
perience that I hope was as helpful for them as it was for me. DR P: One of the pearls of wisdom that we talked about as a We talked about the medical aspects and what we learned. We team the next day is that in situations at the end of life, it’s really talked about pain management and what we learned from our important to get people involved just as if someone was having consulting services. We really spent a lot of time just talking a heart attack. In that case, you would call a cardiologist. If about death and dying, communication at that stage, and what someone had a dropped lung, you would call a surgeon. In a it was like to go home after an experience like that and to talk similar way, you have to treat someone who is terminal, mean- ing death being imminent, as almost a code, in the sense that The palliative care consultation team became actively in- you have to get the people involved who can best provide care volved with the patient when his goals of care changed to com- fort care and when he was identified as dying. The stand- Mr X presented a particular challenge because the dose point that a palliative care team should only become “really of parenteral opioids that he was receiving was clearly beyond involved” if the patients has a “no code” status is contrary to the house officer’s experience and the house officer needed the current concept of palliative care for which the goal is to expert consultation. This case illustrates the critical need move palliative care upstream as part of comprehensive care.
for a clinical pathway for an acute pain crisis and other symp- Although discussion of the management of this case has been tom management in a dying patient.86,87 Such institutional focused on the medical management of the pain crisis, ho- guidelines are important for resource allocation both of staff listic care of the patient and the family needs the expertise of time and ICU bed allocation, enabling continuous moni- the other team members providing psychological support and toring of the high-dose opioid and ketamine infusions. Such behavioral approaches as well as spiritual care.2,96-98 Most of guidelines for management of an acute pain crisis frame a palliative care in oncology is provided by oncological teams.
standard of care, informing both the patient and the health Routine comprehensive symptom assessment and manage- care professionals of a recommended approach, and help to ment may help identify the areas for which palliative care spe- distinguish the appropriate use of rapidly escalating high- cialists may provide direct care to the patient; support the pri- dose opioids and other agents in a dying patient from inap- mary service; or facilitate communications between the patient, propriate strategies of euthanasia and physician-assisted sui- caregivers, and medical team.96,98-101 Institutional guidelines cide (illegal in all states except Oregon).88-90 The Supreme can provide structure for routine palliative care assessment Court decision on physician-assisted suicide endorses aggres- to identify and address unmet palliative care needs and to tran- sive palliative care, even to the point of sedation, in the immi- 2008 American Medical Association. All rights reserved.
(Reprinted with Corrections) JAMA, March 26, 2008—Vol 299, No. 12 1465
PERSPECTIVES ON CARE AT THE CLOSE OF LIFE Financial Disclosures: None reported.
the management of chronic cancer pain: safe and effective starting doses when Funding/Support: The Perspectives on Care at the Close of Life section is made
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2008 American Medical Association. All rights reserved.
(Reprinted with Corrections) JAMA, March 26, 2008—Vol 299, No. 12 1467
Web Sites for End-of-Life Care Resources
related to pain and palliative care.
h t t p : / / c a p c . o r g / p a l l i a t i v e - c a r e - ON END-OF-LIFE CARE
2008 American Medical Association. All rights reserved.
(Reprinted) JAMA, March 26, 2008—Vol 299, No. 12 E1


Assessment of Protein-Ligand binding affinity with Molecular docking approach and Application. 1,2Computer-Chemie-Center, University of Erlangen-Nuremberg, Erlangen, 91052, Germany. Abstract Molecular docking determines the affinity of the ligand molecule towards a target whose 3D structure is known. The most important goals of molecular docking are: 1. Characterization of the bindin

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