Pharmacotherapy for acute pain in children: current practice and recent advances

INTRODUCTION: Acute pain in children may be undertreated. Improved understanding of developmental neurobiology and paediatric pharmacokinetics should facilitate better management of pharmacotherapy. The objective of this review is to discuss current paediatric practice and recent advances with these analgesic agents by using an evidence-based approach. AREAS COVERED: Using PubMed an extensive literature review was conducted on the commonly used analgesic agents in children from 2000 to April 2010. EXPERT OPINION: A multimodal analgesic regimen provides better pain control and functional outcome in children. The choice of pharmacological treatment is determined by the severity and type of pain. However, more research and evidence is required to determine the optimal drug combinations.     

The pharmacokinetics of a long-acting OROS hydromorphone formulation

Importance of the field: New formulations of opiods can provide round-the-clock pain relief to improve pain management and quality of life for patients with chronic pain.

Areas covered in this review: Information and comments on the pharmacokinetic processes associated with a new once-daily formulation of the potent opiod hydromorphone.

What the reader will gain: This review presents an overview of data from several small pharmacokinetic studies to gain a better perspective on the pharmacokinetic properties of a new long-acting formulation of hydromorphone.

Take home message: The development of advanced oral formulation that deliver analgesic drugs over an extended period provides new solutions to improve pain management and quality of life for patients with chronic pain.     

Transmission pathways and mediators as the basis for clinical pharmacology of pain

Introduction: Mediators in pain transmission are the targets of a multitude of different analgesic pharmaceuticals. This review explores the most significant mediators of pain transmission as well as the pharmaceuticals that act on them.

Areas covered: The review explores many of the key mediators of pain transmission. In doing so, this review uncovers important areas for further research. It also highlights agents with potential for producing novel analgesics, probes important interactions between pain transmission pathways that could contribute to synergistic analgesia, and emphasizes transmission factors that participate in transforming acute injury into chronic pain.

Expert commentary: This review examines current pain research, particularly in the context of identifying novel analgesics, highlighting interactions between analgesic transmission pathways, and discussing factors that may contribute to the development of chronic pain after an acute injury.     

Opioid receptor targeting ligands for pain management: a review and update

Importance of the field: Discovery and synthesis of analgesic ligands can potentially improve analgesia, reduce side effects, minimize psychologic dependence and delay analgesic tolerance.

Areas covered in this review: This review covers opioid peptides and analogs and bifunctional opioid ligands, and bifunctional opioid/non-opioid ligands as new, potentially useful analgesics. Several lines of investigation have resulted in potentially useful agents.

What the reader will gain: Modifications of peptide structures have improved opioid receptor affinity, efficacy, stability, half-life and CNS penetrations. Opioid μ receptor agonists have been used to form multi-targeted directed ligands (MDL), which in animal models improve the therapeutic index of the analgesic relative to monovalent potent μ receptor agents. These new opioid ligands are reviewed in detail.

Take home message: Modified opioid peptides and MDL ligands are potentially better analgesics than morphine.     

Chronic pain management issues in the primary care setting and the utility of long-acting opioids

Importance of the field: Chronic/persistent pain – a highly prevalent condition that places a substantial burden on patients in terms of personal suffering, reduced productivity and health care costs – remains inadequately treated in many patients. The purpose of this review is to provide an overview and evaluate the burden and undertreatment of chronic/persistent pain, considerations for choosing an analgesic and the utility of long-acting opioids.

Areas covered in this review: A PubMed search was conducted to identify randomized, placebo-controlled trials evaluating the efficacy and safety of long-acting opioids in chronic pain conditions. The following search terms were used: long-acting opioids, extended-release opioids, controlled-release opioids, sustained-release opioids, and transdermal opioids. The search was limited to randomized, controlled trials published within the last 10 years (1998 – 2008). Studies meeting the following criteria were excluded from review: those focused on a neuropathic pain condition or specific patient subpopulations (e.g., opioid-experienced patients); those conducted outside the USA; and those evaluating a long-acting opioid that is not on the US market at present.

What the reader will gain: The reader will first develop a better understanding of the individual and societal ramifications of undertreated chronic pain. Then, a critical review of safety and efficacy data from well-controlled randomized studies will help readers understand the choices and variables that should be considered when selecting appropriate treatments for patients with chronic pain.

Take home message: Successful management of chronic/persistent pain should be individually tailored to each patient, taking into account his or her pain intensity and duration, disease state, tolerance of adverse events and risk of medication abuse or diversion. The literature supports the efficacy and safety of a number of long-acting opioids for the treatment of moderate to severe chronic pain, demonstrating sustained improvements in pain intensity and pain-related sleep disturbances with these agents.     

An expert opinion on postoperative pain management,with special reference to new developments

Importance of the field: Recently, much attention has been directed towards the effect of opioid-sparing strategies on postoperative morbidity and hospitalization, and on different nociceptive mechanisms involved in various postoperative pain states and surgical procedures. This has resulted in an increased interest in secondary, or adjunct, analgesics and procedure-specific analgesic methods.

Areas covered in this review: The present paper aims to review and discuss recent developments within the field of various adjunct, systemic analgesics and local/regional anesthetic methods for management of postoperative pain, based on evidence from randomized, clinical trials published within the last 5 years.

What the reader will gain: The reader will gain insight into the current role of pregabalin, glucocorticoids and systemic lidocaine for the management of postoperative pain. In addition, the current status of local infiltration analgesia for hip and knee arthroplasty, transversus abdominis plane block for abdominal operations, and the analgesic effect of wound instillation of capsaicin are reviewed.

Take home message: The evidence of a substantial analgesic effect of pregabalin on acute postoperative pain is questionable, and more convincing evidence of the role of glucocorticoids and systemic lidocaine is needed before they should be recommended as analgesics in daily clinical practice. Local infiltration analgesia after hip and knee arthroplasty, transversus abdominis plane block after abdominal operations and local application of capsaicin lend some promise, but there is still a lack of well-performed RCTs to draw any firm conclusions. Procedure-specific analgesic combinations within well-defined rehabilitation paradigms should be explored further to reduce adverse effects associated with the use of conventional analgesic treatment protocols, and to improve postoperative outcome.     

Fixed-dose combinations for emerging treatment of pain

Introduction: Pain is a large and growing medical need that is not currently being fully met, primarily due to the shortcomings of existing analgesics (insufficient efficacy or limiting side-effects). Better outcomes might be achieved using a combination of analgesics. The ratio of the combinations matters and should therefore be evaluated using rigorous quantitative and well-documented analysis.

Areas covered: Advances have been made in understanding the normal physiology of pain processing, including the pathways and neurotransmitters involved. Insight has also been gained about physiological processes that can lead to different ‘types' of pain and the transition from acute to chronic pain conditions. This ‘multimechanistic' nature of most pains is better matched using a ‘multimechanistic' rather than ‘monomechanistic' analgesic approach. Such an approach – and the experimental design and data analysis to assess optimal combinations – is described and discussed.

Expert opinion: There are sound pharmacologic, as well as practical, reasons for using combinations of drugs to treat pain. Compared with single agents, they offer a potential better match to the underlying pain physiology and thus greater efficacy or reduced side effects. The optimal efficacy and side-effect ratio must be determined in a scientifically rigorous manner.     

Targeted approaches to childhood cancer: progress in drug discovery and development

Introduction: Cancer is a leading cause of death in childhood. Encouraging progress has been made in the treatment of childhood malignancies, but there is an unmet need for new drugs to improve survival and reduce treatment-associated toxicities. Drug development in paediatric oncology has specific requirements with regard to the patient population and the regulatory background and presents several unique challenges that need addressing.

Areas covered: This review discusses the current framework of paediatric oncology drug development and some of the specific challenges in pre-clinical and clinical research. The authors discuss the recent developments in the targeting of various signalling pathways. These pathways represent a selection of targets that have been identified by pre-clinical and clinical investigators to be highly relevant in paediatric malignancies.

Expert opinion: The development of targeted agents in paediatric oncology must be driven by knowledge of tumour biology. Predictive and pharmacodynamic biomarkers should be incorporated within paediatric early clinical trials wherever possible. Faster dose-escalation, limited numbers of cohorts and novel adaptive designs can help to make paediatric early clinical trials more efficient. Close collaboration between academic/clinical researchers, the pharmaceutical industry, regulatory bodies and parent groups are crucial in overcoming the challenges associated with paediatric oncology drug development.     

Ketamine for the treatment of chronic non-cancer pain

Importance of the field: Worldwide the number of patients affected by chronic pain is growing and conventional treatment is often insufficient. Recently the importance of the N-methyl-d-aspartate receptor (NMDAR) in the mechanisms and maintenance of chronic pain was established. Ketamine (introduced in the 1960s as an anesthetic) is the most studied NMDAR antagonist in the treatment of various chronic pain syndromes.

Areas covered in this review: The pharmacology, safety and toxicology of ketamine are discussed. Further, electronic databases were scanned for prospective, randomized controlled trials that assessed ketamine's analgesic effect in patients with chronic pain. The focus of this review is on trials published after 2008 that applied long-term intravenous infusions.

What the reader will gain: While most studies on intravenous ketamine show acute analgesic effects, three recent trials on long-term ketamine treatment (days to weeks) demonstrate the effectiveness of ketamine in causing long-term (months) relief of chronic pain. Despite these positive results, further studies are needed on safety/toxicity issues. Other administration modes are less effective in causing long-term pain relief.

Take home message: There is now evidence form a limited number of studies that pain relief lasting for months is observed after long-term intravenous ketamine infusion, suggesting a modulatory effect of ketamine in the process of chronic pain, possibly via blockade of upregulated NMDAR.     

Extended-release formulations of tramadol in the treatment of chronic pain

Introduction: Tramadol is a centrally acting analgesic available throughout the world. Its dual opioid and non-opioid mechanisms of action, favorable efficacy and safety clinical profiles and non-controlled regulatory status in most markets contribute to its widespread use. A drawback of the immediate-release formulation of tramadol (four-times-a-day dosing) might be addressed by an extended-release formulation. Extended-release formulations also can offer advantages in the management of chronic pain: convenience, reduced pill burden (possibly leading to improved compliance) and the attenuation of peaks and troughs in serum concentration (possibly leading to reduced adverse effects).

Areas covered: The authors review tramadol's mechanisms of action and the clinical literature regarding the use of tramadol extended-release formulations for the management of conditions involving chronic pain, such as neuropathic pain syndromes, osteoarthritis and cancer pain.

Expert opinion: Based on the literature cited, extended-release formulations of tramadol seem to offer a rational and important addition to the analgesic armamentarium. As is true for all such options, the benefits and risks must be assessed for each patient.     

Multimodal analgesia in moderate-to-severe pain: a role for a new fixed combination of dexketoprofen and tramadol

Background: Untreated and under-treated pain represent one of the most pervasive health problems, which is worsening as the population ages and accrues risk for pain. Multiple treatment options are available, most of which have one mechanism of action, and cannot be prescribed at unlimited doses due to the ceiling of efficacy and/or safety concerns. Another limitation of single-agent analgesia is that, in general, pain is due to multiple causes. Combining drugs from different classes, with different and complementary mechanism(s) of action, provides a better opportunity for effective analgesia at reduced doses of individual agents. Therefore, there is a potential reduction of adverse events, often dose-related. Analgesic combinations are recommended by several organizations and are used in clinical practice. Provided the two agents are combined in a fixed-dose ratio, the resulting medication may offer advantages over extemporaneous combinations.

Conclusions: Dexketoprofen/tramadol (25?mg/75?mg) is a new oral fixed-dose combination offering a comprehensive multimodal approach to moderate-to-severe acute pain that encompasses central analgesic action, peripheral analgesic effect and anti-inflammatory activity, together with a good tolerability profile. The analgesic efficacy of dexketoprofen/tramadol combination is complemented by a favorable pharmacokinetic and pharmacodynamic profile, characterized by rapid onset and long duration of action. This has been well documented in both somatic- and visceral-pain human models. This review discusses the available clinical evidence and the future possible applications of dexketoprofen/tramadol fixed-dose combination that may play an important role in the management of moderate-to-severe acute pain.     

Juvenile idiopathic arthritis: an update on current pharmacotherapy and future perspectives

Introduction: Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in childhood. Therapeutic advances in the treatment of JIA are occurring at a rapid rate, resulting in more ambitious therapeutic goals and increasing numbers of children experiencing complete clinical remission.

Areas covered: The purpose of this review is to summarize the available treatments for the management of arthritis and systemic features in children with JIA, including current evidence supporting the safety and efficacy of biologic agents and future therapeutic approaches.

Expert opinion: With advances in pharmacotherapy, physical and functional outcomes in children with JIA have improved immensely. The establishment of research consortia among the pediatric rheumatology community has allowed for large controlled studies and enabled a better understanding of the safety and efficacy of these therapeutic agents in children. Long-term safety data remain limited and thus longer, larger safety studies are warranted.     

Combined oral prolonged-release oxycodone and naloxone in opioid-induced bowel dysfunction: review of efficacy and safety data in the treatment of patients experiencing chronic pain

Importance of the field: Despite proven analgesic efficacy, opioid use is associated with frequently dose-limiting bowel dysfunction that seriously impacts patients' quality of life (QoL). Agents used at present to manage opioid-induced constipation do not address the underlying opioid receptor-mediated cause of bowel dysfunction and are often ineffective. There is, therefore, a significant need for more effective treatment options. The combination of the strong opioid oxycodone and the opioid antagonist naloxone has the potential to prevent opioid-induced bowel dysfunction (OIBD) while maintaining analgesic efficacy.

Objective: To review the safety and efficacy of oral prolonged-release (PR) oxycodone/naloxone in the treatment of patients experiencing chronic pain.

Areas covered in this review: A MEDLINE search was done (January 2002 – July 2009) for available literature for prolonged release oxycodone and naloxone in different patient groups. Results were limited to English-language and clinical trials. Data were also obtained from congress materials.

What knowledge the reader will gain: Unmet needs of opioid pain treatment in terms of OIBD, reduced QoL and low treatment compliance, leading to reduced efficacy. A data overview demonstrates the efficacy and tolerability of PR oxycodone/naloxone in the management of severe chronic pain without the burden of severe gastrointestinal adverse events. The combined formulation of a highly effective opioid and an antagonist that acts locally to reduce gastrointestinal side effects is expected to simplify pain management.

Take home message: The combination of PR oxycodone/naloxone offers the potential of maintaining normal bowel function in patients requiring opioid therapy – it is a strong analgesic that is well tolerated.     

Metabolic complications associated with antiretroviral therapy in HIV-infected and HIV-exposed uninfected paediatric patients

Importance of the field: HIV-infection has become a chronic disease in paediatric patients with the potential for long-term survival and exposure to antiretroviral (ARV) therapies for 2 decades longer than HIV-infected adults. On the other hand, the administration of ARV to HIV-infected pregnant women has greatly increased both treatment of HIV infection and prevention of perinatal HIV transmission. Therefore, researches aiming to evaluate the safety of ARV therapies in HIV-infected children as well as in HIV-uninfected infants born to HIV-infected mothers are emerging as a new challenge and urgent priority.

Areas covered in this review: The purpose of this review is to describe some of the more concerning metabolic complications associated with ARV in paediatric population: hyperlactataemia (HLA) syndromes, body shape abnormalities, disorders of glucose homeostasis and dyslipidaemia in HIV-infected children and adolescents. Frequency, risk factors, clinical findings, prevention and intervention strategies of the previously described abnormalities are discussed in depth.

What the reader will gain: This review covers our current understanding of HLA syndromes in ARV-exposed uninfected infants born to HIV-infected mothers.

Take home message: Prevention of these metabolic complications should assume prominence and future researches should address several of the existing treatment gaps.     

Opioid antagonists for pain

Introduction: Opioid receptor antagonists are well known for their ability to attenuate or reverse the effects of opioid agonists. This property has made them useful in mitigating opioid side effects, overdose and abuse. Paradoxically, opioid antagonists have been reported to produce analgesia or enhance analgesia of opioid agonists. The authors review the current state of the clinical use of opioid antagonists as analgesics.

Areas covered: Published clinical trials, case reports and other sources were reviewed to determine the effectiveness and safety of opioid antagonists for use in relieving pain. The results are summarized. Postulated mechanisms for how opioid antagonists might exert an analgesic effect are also briefly summarized.

Expert opinion: Since the comprehensive review by Leavitt in 2009, few new studies on the use of opioid antagonists for pain have been published. The few clinical trials generally consist of small populations. However, there does appear to be a trend of effectiveness of low doses (higher doses antagonize opioid agonist effects). How opioid antagonists can elicit an analgesic effect is still unclear, but a number of possibilities have been suggested. Although the data do not yet support recommendation of widespread application of this off-label use of opioid antagonists, further study appears worthwhile.     

Cyclodextrins: improving the therapeutic response of analgesic drugs: a patent review

Introduction: Cyclodextrins (CDs) are cyclic oligosaccharides that have recently been recognized as useful tools for optimizing the delivery of such problematic drugs. CDs can be found in at least 35 pharmaceutical products, such as anticancer agents, analgesic and anti-inflammatory drugs. Besides, several studies have demonstrated that CD-complexed drugs could provide benefits in solubility, stability and also improve pharmacological response when compared with the drug alone.

Areas covered: The patent search was conducted in the databases WIPO, Espacenet, USPTO, Derwent and INPI, using the keywords cyclodextrin, pain and its related terms (analgesia, hyperalgesia, hypernociception, nociception, antinociception, antinociceptive). We found 442 patents. Criteria such as the complexation of analgesic agents and evidence of improvement of the therapeutic effect were indispensable for the inclusion of the patent. So, 18 patents were selected.

Expert opinion: We noticed that some patents are related to the complexation of opioids, NSAIDs, as well as natural products, in different types of CDs. The use of CDs creates the prospect of developing new therapeutic options for the most effective treatment of painful conditions, allowing a reduction of dosage of analgesic drugs and the occurrence of side effects. Thus, CDs can be an important tool to improve the efficacy and pharmacological profile of analgesic drugs.     

Cebranopadol: a first-in-class potent analgesic agent with agonistic activity at nociceptin/orphanin FQ and opioid receptors

Introduction: Pain is a syndrome of various clinical disorders, which arises from various pathological conditions and which presents significant challenges in both its diagnosis and treatment. There is currently a strong medical demand to develop new therapies with a higher efficacy and a better tolerability profile.

Areas covered: In this review, the authors report on the available data for the pharmacological properties of cebranopadol (GRT6005), a first in-class, potent analgesic compound which acts as an agonist of nociceptin/orphanin FQ peptide (NOP) and opioid receptors. They highlight the in vitro receptor binding studies, as well as the in vivo preclinical results on the analgesic efficacy of cebranopadol obtained in several rodent pain models. The authors also briefly summarize the available data from clinical trials with cebranopadol.

Expert opinion: Cebranopadol displays analgesic, antiallodynic and antihyperalgesic properties in several rat models of acute nociceptive, inflammatory, cancer and neuropathic pain. In contrast to classical opioids, it has a higher analgesic potency in models of neuropathic pain than in acute nociceptive pain. Even at higher analgesic doses, cebranopadol does not induce motor coordination deficits or respiratory depression in rats. Hence, it seems to possess a broader therapeutic window than classical opioids. While it is particularly interesting as a novel, potent bifunctional agonist of NOP/opioid receptors, the outcome of its ongoing and planned clinical trials will be crucial for its future development and potential application in humans.     

Preclinical drug development for childhood cancer

Importance of the field: More effective drugs are needed to treat poor prognosis paediatric malignancies. Development of anticancer agents for childhood cancers faces several unique challenges compared with their adult counterparts.

Areas covered in this review: We demonstrate how recent advances in preclinical drug development may overcome these difficulties and challenges. We explain the role of academia, regulators and industry in this field, address issues with preclinical models and illustrate several examples of biology-driven drug development in childhood cancers.

What the reader will gain: Increased knowledge about preclinical drug development in paediatric oncology including different preclinical models, established preclinical research networks, and relationships among academia, industry and regulators, as illustrated by several examples of targeted agents in childhood solid malignancies.

Take home message: It is anticipated that emerging advanced preclinical models and testing platforms will provide a more efficient, biologically-driven rationale to support the use of targeted therapies in several malignancies such as neuroblastoma, medulloblastoma or high grade glioma which account for the majority of deaths related to childhood cancer.     

Pharmacotherapy of neuroblastoma

Importance of the field: Neuroblastoma, a tumor of the sympathetic nervous system, is the most common extracranial solid tumor of early life. High risk disease in older children remains a therapeutic challenge, despite high-intensity therapy with correspondingly significant short- and long-term toxicities.

Areas covered in this review: We have reviewed therapy for neuroblastoma over the last three decades. This includes cytotoxic chemotherapy, immunotherapy, radionuclides, antiangiogenic compounds, and molecularly targeted agents. We provide a perspective on the incorporation of these drugs into therapy for neuroblastoma.

What the reader will gain: The reader will gain a better understanding of these novel agents and their targets in neuroblastoma. The reader will also gain insight into the need to define through sequential, carefully designed clinical trials, the roles and toxicities of these therapies, especially if the combination of targeted and conventional cytotoxic agents is used.

Take home message: Advanced-stage neuroblastoma in older infants and children remains a disease that is difficult to cure. New, targeted agents may improve both the therapeutic index and the outcome, but are, for the most part, in early development and present a challenge for clinical trial design given both the rarity of this disease and its responsiveness (albeit incomplete) to currently used cytotoxic agents.     

Selective cannabinoid receptor 2 modulators: a patent review 2009 – present

Introduction: The activation of the cannabinoid receptor 2 (CB2) affects a myriad of immune responses from inflammation to neuroprotection, demonstrates analgesic effects and suppresses responses in many animal models of pain. Questions around the involvement of CB1 activation in these effects remain, but efforts have been directed toward the discovery of highly selective CB2 modulators lacking the psychotropic effects of cannabinoids, which are mediated by the CB1 receptor.

Areas covered: This review covers the patent literature which was published since April 2009 on CB2 selective modulators. It provides a general summary of the CB2 biology supporting the interest in CB2 as a drug target, new potential therapeutic indications and the development status of selective CB2 agonists.

Expert opinion: There is a continuous interest in the CB2 receptor as a drug target. Many highly selective compounds of various chemotypes have been identified and their analgesic effects in animal models further support the potential of this mechanism in pain therapy. Several companies have initiated clinical trials. While some of these have been terminated for various reasons, one can anticipate the emergence of new drugs from CB2 modulation once a better understanding around the cannabinoid receptors is gained.