Michael E. Harned

HIV-1 protein Tat potentiation of methamphetamine-induced decreases in evoked overflow of dopamine in the striatum of the rat

HIV-1 infection of the brain can lead to the development of clinical syndromes reminiscent of Parkinsons disease, suggesting that HIV infection may damage nigrostriatal dopamine (DA) neurons. Although the responsible mechanisms have not been well defined, neurotoxic viral proteins, such as Tat, released from infected cells may be involved. Drug abuse is a major risk factor for contracting HIV infection. Methamphetamine (METH), a psychostimulant with high abuse potential, may also be toxic to brain DA neurons. Thus, the combination of METH abuse and HIV infection may lead to substantial alterations in DA neuron functioning. The present experiments examined how Tat, alone and with METH, affects DA release in the striatum. Male rats were given an intrastriatal injection of Tat (25 micro g) or vehicle 24 h before treatment with saline or neurotoxic doses of METH. Seven days later microdialysis studies were carried out to measure potassium- and amphetamine-evoked overflow of DA from the striatum. The Tat treatment alone led to no change in potassium-evoked overflow of DA, a 20% decrease in amphetamine-evoked overflow of DA, and a 16% decrease in striatal DA content. The METH alone led to a 37-42% decrease in striatal DA overflow and content. The combined treatment with Tat and METH led to significantly greater 70-78% decreases in striatal DA overflow and content. These results indicate that Tat enhances METH-induced reductions in striatal DA release and content, possibly in a synergistic manner, and suggest that METH abusers infected with HIV may be at increased risk for basal ganglia dysfunction.

Protection by GDNF and Other Trophic Factors Against the Dopamine-Depleting Effects of Neurotoxic Doses of Methamphetamine

Abstract:  Repeated methamphetamine (METH) administration to animals can result in long‐lasting decreases in striatal dopamine (DA) content. It has previously been shown that glial cell line‐derived neurotrophic factor (GDNF) can reduce the DA‐depleting effects of neurotoxic doses of METH. However, there are several other trophic factors that are protective against dopaminergic toxins. Thus, the present experiments further investigated the protective effect of GDNF as well as the protective effects of several other trophic factors. Male Fischer‐344 rats were given an intracerebral injection of trophic factor (2–10 μg) 1 day before METH (5 mg/kg, s.c., 4 injections at 2‐h intervals). Seven days later DA levels in the striatum were measured using high‐performance liquid chromatography (HPLC). Initial experiments indicated that only intrastriatal GDNF, and not intranigral GDNF, was protective. Thereafter, all other trophic factors were administered into the striatum. Members of the GDNF family (GDNF, neurturin, and artemin) all provided significant protection against the DA‐depleting effects of METH, with GDNF providing the greatest protection. Brain‐derived neurotrophic factor, neurotrophin‐3, acidic fibroblast growth factor, basic fibroblast growth factor, ciliary neurotrophic factor, transforming growth factor‐α (TGF‐α), heregulin β1 (HRG‐β1), and amphiregulin (AR) provided no significant protection at the doses examined. These results suggest that the GDNF family of trophic factors can provide significant protection against the DA‐depleting effects of neurotoxic doses of METH.

A Randomized, Double-Blind Trial Comparing Continuous Thoracic Epidural Bupivacaine With and Without Opioid in Contrast to a Continuous Paravertebral Infusion of Bupivacaine for Post-thoracotomy Pain

OBJECTIVE To compare the results of continuous epidural bupivacaine analgesia with and without hydromorphone to continuous paravertebral analgesia with bupivcaine in patients with post-thoracotomy pain. DESIGN A prospective, randomized, double-blinded trial. SETTING A teaching hospital. PARTICIPANTS Patients at a tertiary care teaching hospital undergoing throracotomy for lung cancer. INTERVENTIONS Subjects were assigned randomly to receive a continuous thoracic epidural or paravertebral infusion. Patients in the epidural group were randomized to receive either bupivacaine alone or in combination with hydromorphone. Visual analog scores as well as incentive spirometery results were obtained before and after thoracotomy. METHODS AND MAIN RESULTS Seventy-five consecutive patients presenting for thoracotomy were enrolled in this institutional review board-approved study. On the morning of surgery, subjects were randomized to either an epidural group receiving bupvicaine with and without hydromorphone or a paravertebral catheter-infused bupvicaine. Postoperative visual analog scores and incentive spirometry data were measured in the postanesthesia care unit, the evening of the first operative day, and daily thereafter until postoperative day 4. Analgesia on all postoperative days was superior in the thoracic epidural group receiving bupivacaine plus hydromorphone. Analgesia was similar in the epidural and continuous paravertebral groups receiving bupivacaine alone. No significant improvement was noted by combining the continuous infusion of bupivacaine via the paravertebral and epidural routes. Incentive spirometry goals were best achieved in the epidural bupivacaine and hydromorphone group and equal in the group receiving bupivacaine alone either via epidural or continuous paravertebral infusion. CONCLUSIONS The current study provided data that fill gaps in the current literature in 3 important areas. First, this study found that thoracic epidural analgesia (TEA) with bupivacaine and a hydrophilic opioid, hydromorphone, may provide enhanced analgesia over TEA or continuous paravertebral infusion (CPI) with bupivacaine alone. Second, in the bupivacaine-alone group, the increased basal rates required to achieve analgesia resulted in hypotension more frequently than in the bupivacaine/hydromorphone combination group, underscoring the benefit of the synergistic activity. Finally, in agreement with previous retrospective studies, the current data suggest that CPI of local anesthetic appears to provide acceptable analgesia for post-thoracotomy pain.

Enhanced effects of 6-hydroxydopamine on evoked overflow of striatal dopamine in aged rats

Nigrostriatal dopamine neurons degenerate during aging, and the excessive loss of dopamine neurons that occurs with Parkinsons disease is usually confined to older individuals. Although 6-hydroxydopamine lesioning of the nigrostriatal dopamine system is a common method for producing animal models of dopamine neuron degeneration, there have been relatively few studies that have examined the effects of 6-hydroxydopamine on the dopamine systems of aged animals. The present experiments were designed to determine if nigrostriatal dopamine neurons in aged rats are more sensitive to the neurotoxic effects of 6-hydroxydopamine than those of younger rats. Young (4-month-old), middle-aged (14-month-old) and aged (24-month-old) Fischer-344 rats were given a single injection of vehicle, 50 or 100 microg 6-hydroxydopamine into the right lateral ventricle. Three to four weeks later in vivo electrochemistry was used to measure potassium-evoked overflow of dopamine in the striatum. In the young rats the 50-microg dose had no significant effect on evoked overflow of dopamine in the striatum or on post-mortem levels of dopamine in the striatum or substantia nigra. The higher dose in the young animals diminished evoked overflow of dopamine as well as tissue levels of dopamine. In the aged rats both doses of 6-hydroxydopamine led to significant decreases in evoked overflow of striatal dopamine and in tissue levels of dopamine in the striatum and substantia nigra. These results suggest that dopamine neurons of aged Fischer-344 rats are more susceptible to the toxic effects of 6-hydroxydopamine than those of younger animals.

Safety concerns with long-term opioid use

ABSTRACT Introduction: The benefits of opioid therapy must be balanced by any adverse effects. In recent years, prescription opioids have been increasingly prescribed, but have also been associated with increased abuse, overdose and death. Areas covered: This review will categorize the common risks of opioid administration. Recognized adverse effects of opioid therapy include constipation, tolerance, endocrinopathies, sleep disorders, cognitive effects, respiratory depression, overdose and addiction. Studies have shown that there is increased risk of overdose and death with higher daily opioid doses, particularly above a morphine equivalent oral daily dose of 100 milligrams. Extended-release/long acting (ER/LA) opioid formulations may be beneficial for the compliant patient, yet may expose a higher risk for abuse if used inappropriately since each tablet carries a larger dose of medication. Expert opinion: Prospective, controlled one-year trials are needed to establish the efficacy and safety profile of chronic opioid therapy. In addition to the well known side effects of chronic opioid therapy, the influence and serious effect of opioids on sleep and central sleep apnea is only recently being investigated. The lowest possible daily opioid must be used to manage chronic pain, and all clinicians should be cautious in the use of daily morphine equivalent doses above 50-100 milligrams.

Trialing and Maintenance Dosing Using a Low-Dose Intrathecal Opioid Method for Chronic Nonmalignant Pain: A Prospective 36-Month Study.

To evaluate low‐dose intrathecal opioid trialing and maintenance with regard to analgesia and psychometric functional capacity.

Trialing of intrathecal baclofen therapy for refractory stiff-person syndrome.

Objective Stiff-person syndrome (SPS) is a rare disorder of the central nervous system characterized by stiffness and muscle spasms that may be progressive in nature. When oral medication is inadequate to control muscle spasticity, intrathecal baclofen may be used. We report a patient with severe SPS and glutamate decarboxylase negative [GAD(−)] (note: GAD(−) indicates the patient has no antibodies to GAD), refractory to oral standard therapies. The patient was effectively trialed with an intrathecal catheter and subsequently treated with chronic intrathecal baclofen, which provided significant relief of spasticity symptoms. Case Report A 48-year-old white man with a history consistent with SPS presented to the clinic. His previous history showed that he met several diagnostic criteria for GAD(−) SPS and had a muscle biopsy positive for myositis. Oral medications were unable to control his muscle spasticity, preventing him from working. The patient received an intrathecal trial using a lumbar approach for placement of a thoracic catheter with an initial baclofen dose of 50 &mgr;g/d. Gradual titration to symptom relief was performed up to 150 &mgr;g/d. Functional evaluation by our physical therapist showed improved motor function, the temporary catheter was removed, and a permanent intrathecal pump placed for intrathecal baclofen infusion. The patient reported excellent symptom relief over the next 6 months and improved activity. Conclusions Refractory SPS is difficult to treat and has few therapeutic options. We report a GAD(−) patient with SPS and resulting debilitating spasticity that was refractory to oral medications who underwent successful continuous intrathecal catheter trial of baclofen over 4 days and subsequently went on to implantation of intrathecal pump. The literature reports only 5 cases of GAD(−) SPS patients treated with intrathecal baclofen therapy, and these resulted in poor long-term success. Our patient completed a 4-day trial of intrathecal baclofen titrated to effect before pump implantation. We advocate continuous intrathecal trialing, as opposed to single-injection technique, to possibly better determine the effective therapeutic dose and ensure posttrialing successful therapy.

The MIST Guidelines: The Lumbar Spinal Stenosis Consensus Group Guidelines for Minimally Invasive Spine Treatment

Lumbar spinal stenosis (LSS) can lead to compression of neural elements and manifest as low back and leg pain. LSS has traditionally been treated with a variety of conservative (pain medications, physical therapy, epidural spinal injections) and invasive (surgical decompression) options. Recently, several minimally invasive procedures have expanded the treatment options.

The Neuromodulation Appropriateness Consensus Committee on Best Practices for Dorsal Root Ganglion Stimulation: Appropriate Use of DRG Stimulation

The Neuromodulation Appropriateness Consensus Committee (NACC) is dedicated to improving the safety and efficacy of neuromodulation and thus improving the lives of patients undergoing neuromodulation therapies. With continued innovations in neuromodulation comes the need for evolving reviews of best practices. Dorsal root ganglion (DRG) stimulation has significantly improved the treatment of complex regional pain syndrome (CRPS), among other conditions. Through funding and organizational leadership by the International Neuromodulation Society (INS), the NACC reconvened to develop the best practices consensus document for the selection, implantation and use of DRG stimulation for the treatment of chronic pain syndromes.

High-Density Spinal Cord Stimulation for the Treatment of Pain in the Rehabilitation Patient

Recent advances in spinal cord stimulation have resulted in new stimulation platforms, which hold great promise in expanding the capabilities of implantable neuromodulation, to produce analgesia for a wider array of patients and patient syndromes. Traditionally, tonic stimulation at low frequencies has resulted in improved analgesia and function for those suffering from neuropathic pain syndromes to include neuropathy, failed back surgery syndrome, complex regional pain syndrome, and angina/vascular insufficiency. Multiple attempts to improve analgesia for those suffering from mechanical or nociceptive pain with stimulation have proven elusive. The application of higher frequency rates in spinal cord stimulation has, in preliminary work, shown promise for low back pain, while maintaining efficacy for neuropathic pain syndromes. This chapter examines one of the theories put forth regarding new stimulation platforms, specifically that frequency alone is not the critical concept, but the combination of pulse width, frequency, and amplitude resulting in increased charge delivery to the target tissue may be key in understanding how to provide better analgesia to patients with nociceptive and neuropathic pain.