CLONIDINE is used extensively now for treatment of intractable neuropathic pain conditions. In the United States, it is approved for epidural application and also has been used intrathecally for treatment of chronic cancer 1and noncancer pain, often in combination with morphine.

Intraventricular analgesics are one of the last resorts of pain management. An intraventricular administration system allows the direct application of morphine to the brainstem and mid brain areas for maximal supraspinal analgesia. This system has been effective in treating head and neck cancer pain. This case report shows the use of combination therapy, specifically morphine and clonidine, to provide pain relief to patients for whom most typical pain therapies have failed.

Case 1

A 60-yr-old man was evaluated at the Stanford Pain Center, Stanford, California, in January 1999 for treatment of intractable facial pain. He had been diagnosed in April 1997 with squamous cell carcinoma of his right tonsil. He underwent radiation therapy, but pain radiating to his mandible and right temporal area developed. Initially, he was treated with opioids, which provided some analgesia. However, with tumor possession and the development of radiation neuritis, his pain worsened.

His treatment now includes carbamazepine, intravenous lidocaine, oral morphine, and levorphanol. A pain cocktail was started, consisting of levorphanol, carbamezepine, and thioridazine. Adverse effects became more prominent, including sedation and cognitive changes.

Because of failure of conservative treatment, a temporary intraventricular catheter was placed on April 16, 1999. His initial rate of intraventricular morphine was 10.4 μg/h. His pain cocktail was discontinued, and he required no breakthrough medications. The intraventricular morphine infusion was increased to 12 μg/h, and the patient reported a pain level of 3 of 10 on a visual analog scale. The intraventricular catheter was connected to a Medtronic SynchroMed EL pump (Minneapolis, MN) on April 19, 1999, and he was discharged from the hospital on April 21, 1999.

The patient experienced rapidly increasing facial pain, which necessitated two hospital stays for monitoring and dosage adjustment. He was readmitted May 20, 1999, for a 50-μg bolus of intraventricular morphine and an increase in rate to 40 μg/h. The next day, a 100-μg bolus was administered and the infusion was increased to 50 μg/h. Finally, the patient had 0.5 μg/h intraventricular clonidine added to his morphine infusion of 50 μg/h, with significant improvement of analgesia. He was discharged on May 24, 1999, with the intraventricular morphine and clonidine infusions. At his follow-up neurosurgical appointment, he reported a 2 of 10 pain level by visual analog scale, as compared with his preoperative level of 9 of 10. He also had markedly reduced sedation.

Follow-up examination showed that the patient remained stable on the same dosage of intraventricular morphine and clonidine for the next 3 months until his death. The morphine elixir was the only adjuvant medication, used at 10 mg every 6 h.

Case 2

A 51-yr-old woman was diagnosed with infiltrating ductal carcinoma of the left breast with brain metastasis after modified radical mastectomy, radiation, and chemotherapy in 1999. Subsequently, chronic lymphedema and pain secondary to brachial plexus compression developed from her left shoulder to her hand. Previous therapies included ketorolac, long-acting opioids, and gabapentin. A morphine infusion produced minimal improvement in analgesia.

The patient was transferred to Stanford Hospital, Stanford, California, for examination for surgical tumor debulking. She presented with a pain level of 10 of 10 on a visual analog scale and loss of left arm motor function. Passive range of motion exacerbated the patient’s pain. Morphine patient-controlled analgesia was started with adjuvant therapies, including ketorolac, lorazepam, and trazodone for sleep. Gabapentin also was increased to a dose of 600 mg three times daily. Twelve hours later, the patient reported increasing left arm pain.

Mass compression of left cervicobrachial region and metastatic compromise of cervical bony structures precluded placement of a cervical epidural or intrathecal catheter. Surgical debulking was determined not to be beneficial. Multilevel dorsal root entry zone lesions were considered, but after consultation between the pain service and neurosurgery, a temporary intraventricular catheter was placed. An intraventricular morphine infusion was started at 10 μg/h. The patient reported significant pain reduction. The intraventricular infusion was increased to 20 μg/h, with no apparent adverse effects. An increased passive range of motion associated with reduced pain also was shown. However, increasing the morphine infusion to 30 μg/h on the third day caused confusion and disorientation. This cognitive impairment resolved after decreasing the intraventricular morphine infusion to 20 μg/h.

The intraventricular infusion then was reformulated to include clonidine. It was restarted with morphine at 20 μg/h and clonidine at 0.05 μg/h. Twelve hours after morphine–clonidine infusion, the patient reported significant pain reduction to 0 of 10 on the visual analog scale and demonstrated an increase in passive range of motion with no incident pain. The patient showed none of the previously observed disorientation in regard to place and time. She was conversant and coherent. Mild sedation resolved over the next 2 days. Her infusion was adjusted to a rate of intraventricular morphine at 20 μg/h and clonidine at 0.1 μg/h. The patient’s improved condition was sustained, and a permanent intraventricular infusion pump was surgically placed. She was discharged to a care facility. The patient remained comfortable and continued to receive the same rates of morphine and clonidine via  the intraventricular pump, with no additional doses of breakthrough oral opioids until her death on November 15, 2000.

Intraventricular medications for cancer pain have been used since the early 1980s. 2–4By placing an intraventricular catheter, smaller amounts of analgesics can be placed at supraspinal sites without hepatic metabolism or interference of the blood–brain barrier. Moreover, intraventricular administration seems more effective than intrathecal administration for head and neck cancer.

Morphine has specific effects at a supraspinal level, including the periaqueductal gray, mesencephalon, dorsal raphe nucleus, and locus coeruleus. 5More recent studies have shown that the concentration of morphine for intraventricular administration are approximately 10 times less than those required for intrathecal administration. 6In a larger intraventricular study with 90 cancer pain patients, a typical starting dosage was 0.25 mg/24 h, increasing to 1 mg daily by 0.25 mg increments. 7Initial intraventricular bolus doses are usually 0.05–0.1 mg.

The application of clonidine for intraventricular administration in humans has not been reported. Clonidine clearly has supraspinal actions at the nucleus tractus solitarius and locus coeruleus to decrease sympathetic drive. The analgesic effects of clonidine seem to be direct activation at spinal α2receptors and do not seem to be mediated by the rostroventromedial medulla. 8Adverse effects, such as sedation and hypolocomotion in animal models, seem to be caused by direct action at the locus coeruleus. 9Clonidine has coanalgesic effects with opiates and local anesthetics when administered intrathecally and epidurally. 10,11Clinical effects, particularly hypotension and sedation, can occur with intrathecal boluses as small as 30 μg. Common intrathecal infusion rates range from 10 to 400 μg/day. The chronic pain patients we have studied usually have had an initial infusion range of 1–5 μg/h.

The relative potency of clonidine in the neuraxis is controversial. A recent study suggests that intrathecal clonidine is approximately 10 times more potent than epidural clonidine for acute noxious stimulation. 12Although clonidine and morphine are different pharmacologic agents, we estimated a relative potency of intraventricular clonidine to be approximately 10 times that of intrathecal clonidine because intraventricular morphine is 10 times that of intrathecal morphine. The mechanism of analgesia from intraventricular clonidine is unclear. In the first patient, direct activation of α2receptors at the trigeminal nerve may have been the site of coanalgesia. In the second patient, activation at the trigeminal nerve for analgesia seems less likely.

These case reports show the usage of multiple agents for pain management, particularly intraventricular clonidine. Combinations of intrathecal infusions for the treatment of chronic pain or cancer pain conditions are becoming much more prevalent. Clonidine seems to be an excellent coanalgesic when opioids need to be increased rapidly and repeatedly to provide analgesia for a fluctuating cancer pain condition. Furthermore, combination therapy helps to minimize adverse effects from either agent.

Clearly, the usage of an intraventricular pump infusing morphine and clonidine should be reserved for intractable and drastic cancer pain conditions. Clonidine has not been approved for intrathecal or intraventricular usage, but the preservative-free mixture should have adverse effects only related to dosing. Intraventricular administration systems can be powerful and effective tools in providing analgesia for severe pain states. Moreover, both patients’ adverse effects were minimized such that they could have improved interaction with their families and more meaningful use of their remaining time.

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