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Modern Applied Statistics With S

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines

Handbook of Pain Assessment

Drugs with low water solubility are predisposed to low and variable oral bioavailability and, therefore, to variability in clinical response. Despite significant efforts to "design in" acceptable developability properties (including aqueous solubility) during lead optimization, approximately 40% of currently marketed compounds and most current drug development candidates remain poorly water-soluble. The fact that so many drug candidates of this type are advanced into development and clinical assessment is testament to an increasingly sophisticated understanding of the approaches that can be taken to promote apparent solubility in the gastrointestinal tract and to support drug exposure after oral administration. Here we provide a detailed commentary on the major challenges to the progression of a poorly water-soluble lead or development candidate and review the approaches and strategies that can be taken to facilitate compound progression. In particular, we address the fundamental principles that underpin the use of strategies, including pH adjustment and salt-form selection, polymorphs, cocrystals, cosolvents, surfactants, cyclodextrins, particle size reduction, amorphous solid dispersions, and lipid-based formulations. In each case, the theoretical basis for utility is described along with a detailed review of recent advances in the field. The article provides an integrated and contemporary discussion of current approaches to solubility and dissolution enhancement but has been deliberately structured as a series of stand-alone sections to allow also directed access to a specific technology (e.g., solid dispersions, lipid-based formulations, or salt forms) where required.

Strategies to Address Low Drug Solubility in Discovery and Development

Opioids are the cornerstone therapy for the treatment of moderate to severe pain. Although common concerns regarding the use of opioids include the potential for detrimental side effects, physical dependence, and addiction, accumulating evidence suggests that opioids may yet cause another problem, often referred to as opioid-induced hyperalgesia. Somewhat paradoxically, opioid therapy aiming at alleviating pain may render patients more sensitive to pain and potentially may aggravate their preexisting pain. This review provides a comprehensive summary of basic and clinical research concerning opioid-induced hyperalgesia, suggests a framework for organizing pertinent information, delineates the status quo of our knowledge, identifies potential clinical implications, and discusses future research directions.

/pdf/opioid-induced-hyperalgesia-a-qualitative-systematic-review-2ry1pe62kk.pdf

Opioid-induced hyperalgesia: a qualitative systematic review.

The mu1, mu2, delta, kappa opioid receptor binding profiles of methadone stereoisomers and morphine.

The English language literature has been reviewed in order to evaluate the present knowledge on morphine's metabolism and pharmacokinetics in children. The majority of preterm neonates are capable of glucuronidating morphine, but birth weight; gestational and postnatal age influence the glucuronidation capability. Term neonates, infants, and children are able to produce morphine glucuronides. For the reported pharmacokinetics parameters a meta-analysis was made; volume of distribution, estimated to be 2.8 +/- 2.6 l.kg-1, seems to be regardless of age, while half-life and clearance were found to be related to age. Half-life was estimated to be 9.0 +/- 3.4 h in pre-term neonates, 6.5 +/- 2.8 h in term neonates aged 0-57 days, and 2.0 +/- 1.8 h for infants and children aged 11 days to 15 years. Clearance was estimated to be 2.2 +/- 0.7 ml.min-1.kg-1 for preterm neonates, 8.1 +/- 3.2 ml.min-1.kg-1 in term neonates aged 0-57 days, and 23.6 +/- 8.5 ml.min-1.kg-1 in infants and children more than 11 days old.

Recommended use of morphine in neonates, infants and children based on a literature review: Part 1—Pharmacokinetics

The indication for morphine use is primarily pain, but also a combined analgesic and sedative effect may be the rationale behind morphine administration. Paediatric morphine regimens have been reported for children with postoperative pain, pain related to cancer, sickle cell crisis pain, burns and AIDS. No dose response curve for morphine in neonates, infants or children has been established, and different levels for the minimum effective plasma concentration have been estimated. The side effects observed in neonates, infants, and children are similar to those observed in adults, and neonates do not seem to be more susceptible to respiratory depression than older children. Despite shortcomings in the knowledge of the pharmacodynamics of morphine, it can be considered safe to administer morphine to neonates, infants or children. Initial regimens has been calculated from the pharmacokinetic parameters of morphine, but treatment must be adjusted according to analgesic effect and incidence of side effects.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1460-9592.1997.tb00488.x

Recommended use of morphine in neonates, infants and children based on a literature review: Part 2–Clinical use

Visceral pain can be difficult to treat with classical μ-opioid agonists and it has been suggested to use opioids with distinct pharmacological profiles. In animal experiments, oxycodone has shown different effects compared to morphine, and clinical observations have shown that oxycodone may occasionally be superior to, e.g., morphine in the treatment of visceral pain. In the current study, we randomised 24 healthy subjects to treatment with either morphine (30 mg), oxycodone (15 mg) or placebo in a crossover study. The experimental pain model involved multi-modal (mechanical, thermal and electrical) pain tests in the skin, muscles and viscera. The pain tests were carried out at baseline and 30, 60 and 90 min after oral administration of the drugs. The model showed effect of the two opioids compared to placebo on all stimulus modalities in all three types of tissues (all P values <0.001). Both opioids attenuated the sensory response mainly to painful stimulations. Morphine and oxycodone were equipotent in pain modulation of the skin and muscles, but oxycodone had superior analgesic effect to both morphine and placebo on the mechanical (P < 0.001) and thermal (P < 0.001) stimulations of the oesophagus. In conclusion, the multi-modal and tissue-differentiated pain model could link findings from animal experiments to clinical findings. A different pharmacological profile of oxycodone compared to that of morphine was shown, and thus oxycodone may be a useful alternative to morphine in the treatment of visceral pain syndromes.

Lona L. Christrup

Papers

The mu1, mu2, delta, kappa opioid receptor binding profiles of methadone stereoisomers and morphine.

Recommended use of morphine in neonates, infants and children based on a literature review: Part 1—Pharmacokinetics

Recommended use of morphine in neonates, infants and children based on a literature review: Part 2–Clinical use

A comparative study of oxycodone and morphine in a multi-modal, tissue-differentiated experimental pain model.

Opioid analgesics as noncompetitive N-methyl-D-aspartate (NMDA) antagonists.