Abstract

In this report, we describe three hospice inpatients with metastatic cancer who were treated with an continuous intravenous infusion consisting of ketamine/morphine/phenobarbital/haloperidol/diphenhydramine (Vena) (K/M/P/H/V) to control refractory pain, insomnia, and agitation. In our study group, we find this combination is effective, safe, and relatively inexpensive for the treatment of uncontrolled pain, insomnia, and agitation in terminally ill patients when the traditional methods are inadequate.

Key words: cancer, terminal life, hospice, refractory symptom

In terminal illness with advanced cancer, “crescendo” pain, insomnia, and agitation are very distressing for the patient and his or her family. In the majority of cases, symptoms are controlled using agents such as morphine, fentanyl, lorazepam, midazolam, or haloperidol. However, there are cases in which these agents are ineffective.

In this retrospective report, we describe our success in using an infusion of ketamine/morphine/phenobarbital/haloperidol/diphenhydramine (Vena) (K/M/P/H/V) in combination to control of refractory symptoms in terminal life care when effective analgesia or sedation could not be achieved in a conventional manner.

Case reports

Case 1

A 70 kg, 71-year-old man was diagnosed with tongue cancer. He ever underwent chemotherapy, radiation therapy, total laryngopharyngectomy, and tracheostomy. Nevertheless, his disease progressed, a large crater shape tumor mass (8x8 cm) with necrosis over upper part of anterior chest wall and tracheostomy obstruction by tumor just prior to admission for hospice care.

During initial evaluation he experienced dyspnea, persistent pain (pain score 7/10), and insomnia. After oxygen treatment (50 % in oxygen), inhalation therapy with sodium bicarbonate and epinephrine were started, the patient had less dyspnea. Initial pain management consisted of 50 μg/hr fentanyl patch 2 patches every other day, morphine, meloxicam, carbamazepine, and amitriptyline. Nevertheless, pain persisted (pain score 5/10) despite increasing 50 μg/hr fentanyl patch to 3 patches every other day. Insomnia was controlled using lorazepam, diazepam, and midazolam. However, these agents were only transient effective or without benefit. Because of continued excruciating pain, insomnia, and irritable, morphine/phenobarbital/haloperidol/diphenhydramine (Vena)/dexamethasone (M/P/H/V/D) continuous intravenous infusion was started on the eighth day of hospitalization. Ketamine was added later due to still intermittent agitation despite increasing phenobarbital dose to 500 mg/day. Upward titration to ketamine (3 mg/mL)/morphine (0.2 mg/mL)/phenobarbital (1.2 mg/mL)/haloperidol (0.05 mg/mL)/Vena (0.3 mg/mL)/dexamethasone (0.03 mg/mL)(K/M/P/H/V/D) 500 mL/day (Table 1), the patient had deep sleep with maintenance of respiration and stable hemodynamics. The infusion was continued until the patient expired eight days later.

 

Table 1 Drug Regimen of Case 1

	Daily dose (mg/day)
Drug	Day 5* to Day 6	Day 7	Day 8 to Day 14	Day 15	Day 16 to Day 17	Day 18	Day 19 to Day 20	Day 21	Day 22 to Day 24	Day 25 to Day 27	Day 28 to Day 35
M	20	80	80	80	100	100	100	100	100	100	100
H	2.5	10	10	10	20	20	25	25	25	25	25
V	30	60	60	60	120	120	150	150	150	150	150
D	----	----	5	5	5	5	5	5	5	10	15
P	----	----	100	300	500	500	600	600	600	600	600
K	----	----	----	----	----	500	500	1000	1500	1500	1500

* Day 5: five days after hospice admission

K: ketamine；M: morphine；P: phenobarbital；H: haloperidol；V: diphenhydramine (Vena)；D: Dexamethasone

 

Case 2

A 35 kg, 56-year-old woman is a case of cervical cancer with metastasis to bone. She also had lumbosacral plexopathy, right femoral fracture status post operation, and a bed sore over sacral region. Because of intractable pain, she received nerve block surgery. However, sharp pain (pain score 8/10) over right thigh was persistent. The excruciating pain and numbness bothered her so much and she cried often. Her pain became so severe that she desired pain control even if it could only be achieved at the cost of sedation. Depression was excluded by the psychiatrist. K/M/P/H/V continuous intravenous infusion was started. The dose of individual drug was gradually titrated (Table 2). The patient died peacefully ten days after initiating ketamine (500 mg/day)/morphine (60 mg/day)/phenobarbital (400 mg/day)/haloperidol (5 mg/day)/diphenhydramine (120 mg/day) therapy.

 

Table 2 Drug Regimen of Case 2

	Daily dose ( mg/day )
Drug	Day 1 to Day 2	Day 3 to Day 23	Day 24 to Day 33
K	250	250	500
M	60	60	60
P	300	400	400
H	5	5	5
V	120	120	120

K: ketamine；M: morphine；P: phenobarbital；
H: haloperidol；V: diphenhydramine (Vena)

 

Case 3

This patient was a 50 kg, 35-year-old single woman with tongue cancer. She ever received lower chin resection surgery, chemotherapy, and radiotherapy. In addition, tracheostomy and feeding gastrostomy were made. Two years after diagnosis, she had submandibular and neck metastasis. Facial swelling and pain developed. She was allergy to fentanyl patch, and the pain in the neck and left cheek was treated with intrathecal PCA (patient control analgesia), consisting of 0.6 mg/mL morphine, 2 % lidocaine with a delivery rate of 2.8 mL/hr. Because of persistent excruciating pain (pain score 9/10) with insomnia despite under PCA treatment, she refused further treatment and requested hospice care.

During hospice admission, we had ever tried additional oral morphine 180 mg/day and intravenous morphine as needed, carbamazepine, amitriptyline, dexamethasone, lorazepam, diazepam, flurazepam, and midazolam to aim at her pain and insomnia. However, these agents showed poor response. Due to persistent pain, insomnia, and agitation, K/M/P/H/V continuous intravenous infusion was started after informed consent by the patient.

After the infusion was started, she had better sleep, less anxious, and clear consciousness; but still pain (pain score 4/10) and irritable mood once awakening. Upward titration to ketamine (2 mg/mL)/morphine (0.2 mg/mL)/phenobarbital (0.8 mg/mL)/haloperidol (0.02 mg/mL)/diphenhydramine (0.24 mg/mL) 500 mL/day (Table 3), the patient was asleep most of the time in a day. Remove intrathecal PCA three days after initiating the infusion. Because the patient requested more sober time during a day, we decreased phenobarbital dose to 200 mg/day. As the disease progressed, intermittent massive bleeding from neck tumor wound happened and consciousness became deteriorated. She died on the 65th days from the first day in hospice.

 

Table 3 Drug Regimen of Case 3

	Daily dose ( mg/day )
Drug	Day 29	Day 30 to Day 31	Day 32 to Day 39	Day 40 to Day 59	Day 60 to Day 64
K	250	500	1000	1000	1000
M	80	100	100	100	100
P	400	800	400	200	300
H	5	10	10	10	5
V	60	120	120	120	30

K: ketamine；M: morphine；P: phenobarbital；

H: haloperidol；V: diphenhydramine (Vena)

 

Discussion

Palliative sedation therapy is often required in terminally ill cancer patients with refractory symptoms to achieve acceptable symptoms relief. Once terminal sedation is initiated, survival can be variable, but generally is brief (from several hours to seven days)^1-5. We used a continuous intravenous infusion of K/M/P/H/V combination with remarkable success. As reported, these three patients died virtually pain-free with little or no agitation and had surprisingly long survival (case 1: 18 days, case 2: 33 days, case 3: 36 days) after initiation of the infusion.

Because this combination of drugs is infrequently used in hospice care, there are several lessons to be learned. First, ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist. Blocking this receptor improves neuropathic pain and allows chronic opioid therapy without the need for increasing doses due to tolerance^6,7. It is used particularly for neuropathic pain, refractory cancer pain, and as adjunct to opioid therapy. In subanesthetic doses, ketamine has dual effects of analgesia and sedation. For sedation and analgesia, effective continuous intravenous infusion dose of ketamine is 5 to 20 μg/kg/min⁸. According to it, doses of ketamine should be 504 to 2016 mg/day for case 1 (actual dose: 1500 mg/day), 252 to 1008 mg/day for case 2 (actual dose: 500 mg/day ), and 360 to 1440 mg/day for case 3 (actual dose: 1000 mg/day). Ketamine does not depress respiratory and cardiovascular systems. Vivid dreams and hallucinations are the most commonly reported problems of ketamine, though rarely the patient can develop a psychosis. Midazolam or haloperidol is commonly given with ketamine to reduce these psychomimetic side effects.

Second, phenobarbital, one of the barbiturates, is in possession of both a hypnotic drug and an anticonvulsant. Barbiturates exert their effect by potentiating the effect of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) on GABAA receptors. They also inhibit the postsynaptic actions of the excitatory neurotransmitter glutamate on non-NMDA receptors⁹. Thus the overall effect of barbiturates is to depress the activity of the central nervous system. Barbiturates do not have analgesic properties and may even be hyperalgesic at low doses, but they can amplify opioid analgesic effect¹⁰. Terminal sedation is performed mainly with midazolam and phenobarbital. Phenobarbital is much cheaper than midazolam and is needed on rare occasions for terminal agitation not responding to midazolam¹. The daily dose of phenobarbital is generally 200-500 mg, except in one patient who increased from 700 mg on the penultimate day to 1200 mg on the day of death⁵. The symbolic association of barbiturates with killing has probably contributed to the reluctance of physicians to use them to relieve symptoms in the terminally ill. However, in our cases receiving phenobarbital there was no evidence of respiratory depression and hemodynamic unsteadiness. Furthermore, the survival of these three cases is long (mean, 29 days) beyond our thinking, which tells us the use of phenobarbital is not associated with shortening of life.

Moreover, haloperidol was added to the infusion to offset side effects associated with ketamine and used to control terminal restlessness. Dexamethasone was administered adjunctively for pain relief. With regard to diphenhydramine (Vena), it can prevent akathisia produced by haloperidol and make use of its sedative action.

In summary, K/M/P/H/V mixture by continuous intravenous infusion in our patients achieves a strategy for balancing drug synergy, reduction of side effects, efficacy, and safety. For patients in hospice care, this combination should be considered as a therapeutic option in specific circumstances.