Application of Ultrahigh Doses of Morphine in Systemic Multiple Epithelioid Hemangioendothelioma without Addiction: A Case Report

Morphine is a potent opioid which is commonly used for relieving cancer pain with strong analgesic properties. Epithelioid hemangioendothelioma (EHE), a rare vascular tumor that can cause severe chronic pain, is usually diagnosed in a surgical biopsy. We describe ultrahigh doses of morphine used in a case of a 17-year-old male who suffered from severe chest pain with systemic multiple EHE. The total dosage of morphine was as high as 92,530 mg given within 164 days. However, we observed no indications that the patient was addicted.


Case Overview
In August 2013, a 13-year-old man presented to the hospital with the left knee pain after a long walk. His medical and family history revealed no major medical problems. Multiple bone tumors of lower extremity was diagnosed with X-ray examination, after that both multiple body Computed Tomography (CT) and        and carbamazepine 200 mg (100 mg orally per 12 h) every day to prevent a rapid rise in the amount of morphine administered. However, the daily dose of morphine still increased quickly to meet the patient's needs for analgesia, the pain score was assessed every day, and the dosage of morphine increased 10 mg per day on average. In the early November 2017, the daily amount of morphine had risen to 1000 mg (1000 mg morphine diluted to 150 ml into a PCIA device, parameters set to a loading dose of 3 ml, a background dose of 5 ml, and a unit dose of 3 ml per 15 min). An opioid tolerance (OT) was diagnosed, and opioid addiction and withdrawal tests were conducted. For example, in the Addiction Severity Index Questionnaire [14], the patient's rating scale was only 1 score and the interviewer severity rating got 2 points, indicated that the patient was not addictive. In the Prescription Opioid Addiction Treatment Study [15], result showed that the patient did not need to be treated for addiction. In the Opioid Withdrawal Scale [16], the patient was mental balance, only presented severe pain in the whole body without other symptoms such as sanity disorder or fidgety. In this case, a patient controlled epidural analgesia (PCEA) device was inserted to the 6/7 segment of the thoracic spine, and a dose of morphine 200 mg and ropivacaine 200 mg were administered via an epidural catheter (diluted to 150 ml, with a background dose of 3 ml, and an unit dose of 3 ml per 15 min). This provided adequate pain relief for more than one week, and the daily dosage of intravenous morphine dropped to about 800 mg. However, opioid-induced hyperalgesia (OIH) was diagnosed at the second week after the implantation of the PCEA, we started to increase the dose of epidural morphine for 10 mg every day, but that could not effectively relieve the pain from lower limbs. Subsequently, the intravenous morphine dose started to rise again (almost 20 mg/day for addition). At the beginning of the fifth month, the daily total amount of morphine administered reached 1500 mg (venous 1100 mg and epidural 400 mg on average), but still could not effectively relieve the pain. Since ongoing tests continuously excluded the possibility of addiction, an extra single intravenous injection of morphine 100 mg (basically once every 8 h) was given whenever both PCIA and PCEA could not provide sufficient analgesia.
The patient died from multiple organ failure (MOF) in late December 2017. Although he was very weak in the last days, he did not complain of pain. The total dosage of all analgesics administered was: morphine 92,530 mg, chlorpromazine 2525 mg, carbamazepine 19,200 mg, and ropivacaine 14,200 mg within 164 days (Table 1).

Discussion
Surgical resection is one of the effective ways to treat EHE [17] [18]. It is reported that the 5-year survival rate after surgical excision is approximately 75% [19], and this provides a good basis for patients to choose surgical treatment. However, complete resection is impossible in patients with systemic multiple EHE, and surgery cannot radically cure the pain [20]. In this report, the patient was symptom-free for 4 years; although the surgery removed the pain of the lesion sites, it did not solve the patient's pain symptoms. On the contrary, the operation caused the peripheral sensitization of pain and aggravated the progress of obstinate pains. In this condition, the palliative therapy was determined, but first of all, it was very important to use an effective measure to deal with pain that could positively affect the quality of life of the patient. It is well-recognized that morphine is the safest and most effective analgesic for releasing chronic, cancer pain, and there is no ceiling effect [21]. Though extended exposure to morphine can lead to some drug-related adverse reactions such as analgesic tolerance, drug addiction, hyperalgesia, etc., a research suggests that long-term, high-dose morphine use was well-tolerated, and could improve patient's life quality without affecting life expectancy [22]. In a nine-month study, Chatham [23] reported that a daily dose of morphine over 1200 mg was safe. Moreover, Lin [24] found that morphine could also induce the apoptosis of cancer cells in a chronic high-dose morphine treatment study, and this effect was beneficial to patient recovery. Thus, we defined the dose of morphine according to the patient's need. In this case, the initial application of morphine was directly prescribed by the anesthesiologist. But with the aggravation of patients' pain, our anesthesia department was unable to provide sufficient amount of morphine, thus the anesthesiologist communicated with the patient's chief physician every morning after pain assessment, and informed the doctor in charge of the expected morphine of the day. The nurse on duty went to the pharmacy to receive the medicine with the red prescription, then told the anesthesiologist to give analgesic treatment and psychotherapy.
Currently, both OT and OIH are common in patients receiving long-term opioid management for cancer pain. OT is defined as a physiological state in which the body adapts to the medication after frequent exposure and requires higher doses to achieve the same effect. OIH is a phenomenon of enhanced pain sensitization to stimulation [25]. The mechanisms responsible for OT and OIH are complicated, including mesenchymal stem cells attenuation, glutamate release in the spinal cord, descending facilitation, etc. [26] [27] [28]. Drugs such as cyclooxygenase-2 inhibitors, ketamine, and dextromethorphan have been proposed to help manage OIH [27] [28], but there are anxieties about the potential organ damages caused by these medicines. To reduce the interactions among a variety of drugs, and to acquire an accurate estimation of analgesia addiction, we did not add other medications to deal with these complications.
Addiction is another common adverse reaction after long-term opioid treatment. Addicted patients usually exhibit drug-seeking behavior due to depression or anxiety [29]. The activation of the mesolimbic dopaminergic pathway, the inflammation and degeneration of neurons, including long-term potentiation and long-term depression of the glutamatergic synapses are thought to be contributed to the development of addiction [29] [30]. Since our patient was always clear in consciousness, and did not appear any abnormal features suggestive of addiction, we concluded that the amount of morphine should not be limited under strict addiction assessments.

Conclusion
In summary, our practice represents a prolonged ultrahigh dose of morphine or comparative studies are needed to evaluate the outcome of this approach, and a well-constructed evaluation scale such as the limits of OT and OIH should be adopted to assess the potential complications as well.