Intrathecal Therapy for Chronic Pain: A Review of Morphine and Ziconotide as Firstline Options.

OBJECTIVES: To evaluate the evidence for morphine and ziconotide as firstline intrathecal (IT) analgesia agents for patients with chronic pain. METHODS: Medline was searched (through July 2017) for "ziconotide" or "morphine" AND "intrathecal" AND "chronic pain," with results limited to studies in human populations. RESULTS: The literature supports the use of morphine (based primarily on noncontrolled, prospective, and retrospective studies) and ziconotide (based on randomized controlled trials and prospective observational studies) as first-choice IT therapies. The 2016 Polyanalgesic Consensus Conference (PACC) guidelines recommended both morphine and ziconotide as firstline IT monotherapy for localized and diffuse chronic pain of cancer-related and non-cancer-related etiologies; however, one consensus point emphasized ziconotide use, unless contraindicated, as firstline IT therapy in patients with chronic non-cancer-related pain. Initial IT therapy choice should take into consideration individual patient characteristics (e.g., pain location, response to previous therapies, comorbid medical conditions, psychiatric history). Trialing is recommended to assess medication efficacy and tolerability. For both morphine and ziconotide, the PACC guidelines recommend conservative initial dosing strategies. Due to its narrow therapeutic window, ziconotide requires careful dose titration. Ziconotide is contraindicated in patients with a history of psychosis. IT morphine administration may be associated with serious side effects (e.g., respiratory depression, catheter tip granuloma), require dose increases, and cause dependence over time. CONCLUSION: Based on the available evidence, morphine and ziconotide are recommended as firstline IT monotherapy for cancer-related and non-cancer-related pain. The choice of first-in-pump therapy should take into consideration patient characteristics and the advantages and disadvantages of each medication.

A Comprehensive Algorithm for Management of Neuropathic Pain.

BACKGROUND: The objective of this review was to merge current treatment guidelines and best practice recommendations for management of neuropathic pain into a comprehensive algorithm for primary physicians. The algorithm covers assessment, multidisciplinary conservative care, nonopioid pharmacological management, interventional therapies, neurostimulation, low-dose opioid treatment, and targeted drug delivery therapy. METHODS: Available literature was identified through a search of the US National Library of Medicine's Medline database, PubMed.gov. References from identified published articles also were reviewed for relevant citations. RESULTS: The algorithm provides a comprehensive treatment pathway from assessment to the provision of first- through sixth-line therapies for primary care physicians. Clear indicators for progression of therapy from firstline to sixth-line are provided. Multidisciplinary conservative care and nonopioid medications (tricyclic antidepressants, serotonin norepinephrine reuptake inhibitors, gabapentanoids, topicals, and transdermal substances) are recommended as firstline therapy; combination therapy (firstline medications) and tramadol and tapentadol are recommended as secondline; serotonin-specific reuptake inhibitors/anticonvulsants/NMDA antagonists and interventional therapies as third-line; neurostimulation as a fourth-line treatment; low-dose opioids (no greater than 90 morphine equivalent units) are fifth-line; and finally, targeted drug delivery is the last-line therapy for patients with refractory pain. CONCLUSIONS: The presented treatment algorithm provides clear-cut tools for the assessment and treatment of neuropathic pain based on international guidelines, published data, and best practice recommendations. It defines the benefits and limitations of the current treatments at our disposal. Additionally, it provides an easy-to-follow visual guide of the recommended steps in the algorithm for primary care and family practitioners to utilize.

Ziconotide Combination Intrathecal Therapy for Noncancer Pain Is Limited Secondary to Delayed Adverse Effects: A Case Series With a 24-Month Follow-Up.

OBJECTIVES: The efficacy and safety of ziconotide as a single agent has been evaluated in few short-term clinical trials and open-label studies. Ziconotide use is challenging given its adverse effect (AE) profile. The objective of this study is to describe the long-term efficacy and AEs of ziconotide used as an adjunct to other intrathecal (IT) agents in chronic noncancer pain patients. MATERIALS AND METHODS: A case series of chronic noncancer pain patients who had suboptimal pain control from IT therapy. Ziconotide was introduced in the IT infusion mixture after a successful ziconotide trial. Pain scores, IT doses, as well as AEs were recorded and analyzed from trial to initial ziconotide infusion and up to 24 months. RESULTS: Fifteen patients underwent ziconotide trials. Four subjects failed the trial, and 11 proceeded to continuous ziconotide treatment. Seven out of 11 patients experienced AEs resulting in ziconotide discontinuation. Two of the seven subjects who required discontinuation of ziconotide had improved pain. Four subjects were able to continue IT ziconotide through 24 months. CONCLUSIONS: A high incidence of AEs limits the usefulness of IT ziconotide as adjunct therapy. Our results are limited by the size of our patient population; however, they represent a long follow-up period, which is limited in most current publications on this IT peptide. While ziconotide is a needed IT agent, more studies are necessary to better understand the factors that would improve the treatment to trial ratio as well as the long-term efficacy of IT ziconotide treatment.

Intrathecal therapy for chronic pain: current trends and future needs.

The management of chronic pain continues to pose many challenges to healthcare providers. Intrathecal drug delivery systems (IDDS) provide an effective therapy for patients suffering from chronic pain intractable to medical management. However, the clinical growth of intrathecal therapy continues to face many challenges, and is likely underutilized secondary to its high-complexity and limited reimbursement. The clinical utility of IDDS remains limited by lack of prospective randomized, placebo-controlled studies. In addition, there remains a need to enhance physician knowledge on the pharmacodynamics and pharmacokinetics of intrathecal drug delivery and promote further research into this field and drug delivery modalities. The purpose of this article is to provide a comprehensive review of the determinants of successful intrathecal drug delivery with an emphasis on its use in noncancer pain.

Current Perspectives on Neurostimulation for the Management of Chronic Low Back Pain: A Narrative Review.

Neurostimulation techniques for the treatment of chronic low back pain (LBP) have been rapidly evolving; however, questions remain as to which modalities provide the most efficacious and durable treatment for intractable axial symptoms. Modalities of spinal cord stimulation, such as traditional low-frequency paresthesia based, high-density or high dose (HD), burst, 10-kHz high-frequency therapy, closed-loop, and differential target multiplexed, have been limitedly studied to determine their efficacy for the treatment of axial LBP. In addition, stimulation methods that target regions other than the spinal cord, such as medial branch nerve stimulation of the multifidus muscles and the dorsal root ganglion may also be viable treatment options. Here, current scientific evidence behind neurostimulation techniques have been reviewed with a focus on the management of chronic axial LBP.

Weakness of whole muscles in mice deficient in Cu, Zn superoxide dismutase is not explained by defects at the level of the contractile apparatus.

Mice deficient in Cu,Zn superoxide dismutase (Sod1 (-/-) mice) demonstrate elevated oxidative stress associated with rapid age-related declines in muscle mass and force. The decline in mass for muscles of Sod1 (-/-) mice is explained by a loss of muscle fibers, but the mechanism underlying the weakness is not clear. We hypothesized that the reduced maximum isometric force (F o) normalized by cross-sectional area (specific F o) for whole muscles of Sod1 (-/-) compared with wild-type (WT) mice is due to decreased specific F o of individual fibers. Force generation was measured for permeabilized fibers from muscles of Sod1 (-/-) and WT mice at 8 and 20 months of age. WT mice were also studied at 28 months to determine whether any deficits observed for fibers from Sod1 (-/-) mice were similar to those observed in old WT mice. No effects of genotype were observed for F o or specific F o at either 8 or 20 months, and no age-associated decrease in specific F o was observed for fibers from Sod1 (-/-) mice, whereas specific F o for fibers of WT mice decreased by 20 % by 28 months. Oxidative stress has also been associated with decreased maximum velocity of shortening (V max), and we found a 10 % lower V max for fibers from Sod1 (-/-) compared with WT mice at 20 months. We conclude that the low specific F o of muscles of Sod1 (-/-) mice is not explained by damage to contractile proteins. Moreover, the properties of fibers of Sod1 (-/-) mice do not recapitulate those observed with aging in WT animals.

The effect of cleft palate repair on contractile properties of single permeabilized muscle fibers from congenitally cleft goat palates.

Inherent differences in the levator veli palatini (LVP) muscle of cleft palates before palatoplasty may play a role in persistent postrepair velopharyngeal insufficiency (VPI). Contractile properties of LVP muscle fibers were analyzed from young (2-month) normal (YNP), young congenitally cleft (YCP) and again on the same YCP subjects 6 months after palatoplasty, mature repaired palate (MRP). The cross-sectional area and rate of force development (ktr) were measured. Specific force (sF(0)) and normalized power (nP(max)) were calculated. Using k(tr) to determine fiber type composition, YNP was 44% type 1 and 56% type 2, while YCP was 100% type 2. Two MRP subjects shifted to 100% type 1; 1 demonstrated increased resistance to fatigue. No differences in sF(0) were observed. nP(max) increased with presence of type 2 fibers. The persistent state of type 2 fibers following palatoplasty leads to increased fatigue in the LVP of MRP subjects and may cause VPI symptoms.

Contractile properties of single permeabilized muscle fibers from congenital cleft palates and normal palates of Spanish goats.

BACKGROUND: Analysis of the composition of muscle fibers constituent to a cleft palate could provide significant insight into the cause of velopharyngeal inadequacy. The authors hypothesized that levator veli palatini muscle dysfunction inherent to cleft palates could affect the timing and outcome of cleft palate repair. METHODS: Single, permeabilized muscle fibers from levator veli palatini muscles of three normal (n = 19 fibers) and three chemically induced congenital cleft palates (n = 21 fibers) of 14-month-old goats were isolated, and contractile properties were evaluated. The maximum isometric force and rate constants of tension redevelopment (ktr) were measured, and the specific force and normalized power were calculated for each fiber. RESULTS: The ktr measures indicate that cleft fibers are predominantly fast-fatigable; normal fibers are slow fatigue-resistant: after a 10-minute isometric contraction, fibers from cleft palates had a loss of force 16 percent greater than that from normal palates (p = 0.0001). The cross-sectional areas of the fibers from cleft palates (2750 +/- 209 microm2) were greater (p = 0.05) than those from normal palates (2226 +/- 143 microm2). Specific forces did not differ between the two groups. Maximum normalized power of fibers from cleft palates (11.05 +/- 1.82 W/l) was greater (p = 0.0001) than fibers from normal palates (1.60 +/- 0.12 W/l). CONCLUSIONS: There are clear physiologic differences in single muscle fibers from cleft palates and normal palates: cleft palate fibers are physiologically fast, have greater fatigability, and have greater power production. Detection of functional and/or fiber type differences in muscles of cleft palates may provide preoperative identification of a patient's susceptibility to velopharyngeal inadequacy and permit early surgical intervention to correct this clinical condition.