Long-Term High-dose Oral Morphine in Phantom Limb Pain with No Addiction Risk

INTRODUCTION

Chronic phantom limb pain (PLP) is a neuropathic pain located in the missing/amputated limb. The patient usually describes as having tingling sensations in a topographical representing area resembling pre-amputation limb.[1] The incidence of PLP post-amputation varies from 49% to 88%.[2345] Phantom pain is difficult to treat as the exact basis of pain mechanism is still unknown. Various methods of treatment for PLP have been described, including pharmacological (NSAIDs, opioids, antiepileptic, antidepressants) and non-pharmacological (TENS, sympathectomy, deep brain stimulation and motor cortex stimulation).[6] Opioids are used for the treatment of neuropathic pain. Opioids have shown efficacy in the treatment of PLP and may potentially influence cortical reorganization. The use of opioids for the management of neuropathic pain has been supported in several guidelines, including the American Pain Society (APS) and the American Academy of Pain Medicine (AAPM).[78] The dose of opioid is based on its effect, and maximum dose has not been prescribed. However, exceptionally high dose remains a concern. We report a case where a patient receiving high-dose oral morphine for chronic cancer pain did not demonstrate any signs of addiction.

CASE REPORT

A 72-year-old male, a case of malignant mesenchymal tumor of upper one-third of right tibia, evaluated first 13 years ago by the surgical oncology unit, was found to have localized disease with PET negative for any distant metastasis. He underwent right above knee amputation under combined spinal epidural anesthesia. For postoperative pain, epidural morphine 3 mg twice per day was administered for the next five days and he was totally pain-free. He was discharged on oral morphine 5 mg four hourly, paracetamol 1000 mg six hourly and Bisacodyl 10 mg at bedtime. After one week, the patient complained of severe pain, squeezing in nature with occasional pins and needle sensation in the amputated limb starting from palmar aspect of the right foot radiating to dorsal aspect and subsequently to the entire right leg associated with heaviness in the limb suggestive of PLP. His pain score was 8 on a visual analog scale (VAS). He was started on oral morphine 10 mg four hourly, which needed progressive upward titration to 120 mg four hourly over a period of four weeks. Once pain control was optimal (VAS of 1-2), he was maintained on monthly follow up for the next one year with a stable oral morphine dose, conferring pain relief of 80-90% with VAS of 1-3. Thereafter, he started complaining of increased pain, which required an increase in morphine dose gradually to 300 mg four hourly to achieve a VAS <4. During subsequent follow up, his pain was inadequately controlled, which warranted epidural analgesia with 0.125% bupivacaine infusion for pain relief. This provided adequate pain relief with no phantom limb sensations. However, any attempt to wean dose of oral morphine caused rebound pain and features of opioid withdrawal. Hence chemical lumbar sympathectomy was planned under fluoroscopic guidance at the level of L2 with 4 ml of phenol. Following this procedure, patient had partial pain relief (VAS: 4/10). Dose of oral morphine was gradually decreased to 240 mg four hourly. In view of persistent pain, other modalities of interventional chronic pain management techniques like the placement of spinal cord stimulator, neuromodulator, and nerve blocks like lumber plexus block (right), sciatic nerve block (right) were also attempted over the next few years. However, pain relief was inadequate and VAS score remained >4. Dose of morphine was gradually titrated to 540 mg every four hourly. With this dose of morphine, there were concerns regarding opioid dependence/addiction. These concerns were addressed by gradual withdrawal of morphine under in-patient supervision. Withdrawal of morphine only caused rebound pain and patient did not manifest any features to suggest addiction. A formal psychiatry opinion was sought to confirm the findings administered following tests for assessment such as verbal adult intelligence scale (VAIS), Bender-Gestalt test; Draw a person test and Rorschach inkblot test. The results of these tests revealed that the patient has average intelligence with cluster B and C traits, and ruled out possible drug-seeking behavior. Presently, the patient is under follow up in our pain clinic and taking 540 mg of oral morphine every four hourly without any signs of toxicity or features of opioid dependence. Patient is actively involved in his routine daily activities. He enjoys good family support and his depression is well controlled with medications.

DISCUSSION

The ceiling dose of morphine for chronic cancer pain has not been reported. The dose of morphine is titrated to its optimal pain relief and occurrence of unmanageable side effects. The need of high-dose morphine for PLP has been earlier reported.[9] Our patient had an intermittent break through phantom pain needing progressive dose escalation. Trial of optimal dose of adjuvants for neuropathic pain and interventional pain management techniques such as epidural local anesthetics and chemical sympathectomy did not confer satisfactory and sustained pain relief. Hence the patient needed gradual upward titration of morphine dose, which is categorized as high-dose morphine (morphine >299 mg/day of oral morphine equivalent).[10] High-dose morphine required in our patient was probably the optimal dose for the patient for PLP. It may possibly be attributed to pharmacogenomic factors affecting both pharmacokinetic and pharmacodynamic aspects of morphine metabolism.

The high dose of morphine requirement could be also secondary to addiction potential or due to opioid-induced hyperalgesia. The addiction potential in properly selected patients, managed diligently in a chronic cancer pain management setting is a seldom occurence.[11] Addiction is a complex phenomenon involving genetic and biopsychosocial factors. It is characterized by having craving, loss of control over the substance use and compulsion to use drug despite harmful consequences. The incidence of addiction is less than 1% in cancer patients receiving opioids.[12] Though very high dose may have a probability of addiction, their incidence is quite low. Psychiatric evaluation done in this patient was negative for any addiction potential. Pseudo-addiction is a behavior that resembles addiction, but actually it is an iatrogenic syndrome due to undertreatment or anxiety related to undertreatment. Patient exhibits drug-seeking behavior due to poorly controlled pain and often become obsessed with obtaining and taking opioids for control of their pain. Pseudoaddiction must be ruled out whenever one suspects addiction.[13] The optimal dose may be assessed by withholding morphine. If the pain intensity increases and resumption of previous dose leads to adequate pain relief, it indicates that the patient's dose requirement is truly high. Moreover, our patient was stable on current dose for the last seven years without craving or abnormal behavior suggestive of addiction.

Opioid-induced hyperalgesia (OIH) is occurrence of paradoxical hyperalgesia in patients getting opioid for pain relief. The type of pain may or may not be similar to pre-existing pain. The proposed mechanism of OIH includes involvement of central glutaminergic system, raised spinal dynorphins, descending facilitation, genetic polymorphism of catechol-o-methyltransferase, and decreased reuptake and enhanced nociceptive response. OIH should be suspected when opioid effect wears off in absence of disease progression and increased intensity of pain with increasing dose of opioid.[14] On evaluation, this patient did not have features suggestive of OIH.

Hence we conclude ongoing and thorough assessment of pain along with analgesic titration is a must in cancer pain management. When prescribed under supervision, with frequent pain assessment and dose titration, addiction has not been found with morphine in PLP even at a very high dose.