Researchers have evidence of misuse for drugs prescribed to treat chronic pain in children

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Decisions to prescribe children drugs to treat chronic pain are not guided by sufficient, high quality evidence, according to an important new study published today.

Published as part of a special collection of systematic reviews in the Cochrane Library and recently summarised in the journal PAIN, the overview highlights a dearth of information available about treating childhood chronic pain and concludes that much more needs to be done to improve the quality and quantity of evidence available.

It is led by researchers at the University of Bath in collaboration with an international team of researchers and physicians.

In adults, chronic pain lasting for three months or more is known to have a devastating effect.

What is less well known is that one in five children also report chronic pain, which is both distressing and disabling for children and their parents.

But the new study reveals a stark contrast between the evidence available for the drugs used to treat adults with chronic pain, compared with that conducted in children.

For adults with chronic pain, 300,000 patients have been studied in hundreds of individual randomised control trials.

Yet only 393 children have participated in just six trials ever undertaken.

The research is a summary of all available systematic reviews of studies in this area and is supported by the National Institute for Health Research (NIHR), Versus Arthritis and also involves Bath’s Centre for Pain Services (part of the RUH Foundation Trust).

The team who prepared the overview stress that lack of evidence does not mean evidence of no effect.

But they argue there has been very little investment in researching which drugs can best help children with chronic pain and suggest that this issue should be urgently addressed to increase confidence that children are getting the best treatment.

They describe the disparity of knowledge between adults and children – a ratio of around 1000:1 – as ‘unacceptable’ and suggest that the lessons learnt from research conducted on adults cannot ‘simply be applied to children’ whose biology and metabolism work differently.

The most common types of chronic pain experienced by children include recurrent abdominal pain, headaches and migraines, and musculoskeletal pain.

Children who suffer from chronic pain regularly miss school, become isolated and have more anxiety and depression compared to children without pain.

Drug therapy is typically the first resort for treatment.

Professor Christopher Eccleston, Co-ordinating Editor for the Cochrane Pain, Palliative and Supportive Care Review Group and Director of the Centre for Pain Research at the University of Bath, who led the overview, explained:

“Overall, there is no high-quality evidence to help us understand the efficacy or safety of the common drugs used to help children with chronic pain.

The lack of data means that we are uncertain about how to optimally manage pain. Doctors, children and their families all deserve better.

“This study is a collective effort from 23 leading researchers and physicians from around the world.

Healthcare policy-makers need to grapple this issue if we are to break down the barriers that exist to producing sufficient evidence in paediatric chronic pain pharmacotherapy.”

The team acknowledges that there are practical and ethical barriers to conducting randomised control trials on children, but suggest that these are no different from other areas of paediatric pharmacological research.

Co-author Dr. Emma Fisher, Versus Arthritis Research Fellow from the Centre for Pain Research at the University of Bath, added: “Children are not just small adults so we cannot simply extrapolate evidence acquired from adults and use it in children.

“With the evidence available currently we cannot say for sure whether the drugs used are the best approach.

Yet at the current rate of clinical trial reporting – only one every 3.5 years – it would take us over 1,000 years to have a good enough evidence base to properly inform decisions.

This lack of knowledge requires new funding and urgent attention.”

Stewart Long, Director of Involvement and Services, at Versus Arthritis who supported the study, said: “Living with chronic pain can have a profound physical, emotional and psychological impact, particularly in children.

It can stop them joining in things other young people do and affect development of friendships.

This can lead to isolation, making children more likely to suffer from anxiety and depression and affect their ability to fulfil their potential and maintain their future aspirations.

“Despite the scale and impact of chronic pain, as well as its socio-economic cost, there is a serious lack of research into effective treatments for adults and children alike.

We urgently need chronic pain to be prioritised in policy, funding and research so that the millions of people living in pain today, regardless of their age, are better supported.”

Dr. Jacqui Clinch, Medical lead consultant for young people at the national Bath Centre for Pain Services explained: “Within BCPS we see and treat children and adolescents from across the UK who have suffered pain and pain associated difficulties often for years.

These young people, in addition to overwhelming pain, develop sleep disturbance, memory and concentration difficulties, muscle weakness, cramps, numbness, nausea, and many other pain related symptoms.

“They transform from physically and socially active individuals to missing school, physically inactive and housebound.

In short, their lives, and those of their loved ones, fall apart. Our unique dedicated multidisciplinary team has delivered successful rehabilitation for these young people and carers for over 20 years.

As part of the international pain community, we strive to optimise research into both further understanding pain pathways in young people and exploring new interventions to alleviate suffering in this vulnerable population and their families.”

Other non-drug-based treatments are also available to children and adolescents with chronic pain.

Psychological therapies, such as cognitive behavioural therapy (CBT), show small effects at reducing pain and disability in this population, but once again the evidence needs to be improved.

The researchers suggest funding and incentives are needed to drive this field forwards in order to deliver evidence-based research that doctors treating patients can reliably use to inform their decisions.


There are currently no general guidelines on opioid usage for analgesia in the pediatric population. The Centers for Disease Control and Prevention (CDC) opioid prescribing guideline for chronic pain states there is limited evidence for children and adolescents, and the population is outside the scope of the guideline.1 Thus, pediatric practices have largely been adapted from the adult population. Subsequently, medication safety concerns have made prescribing and monitoring opioids in pediatrics challenging. A number of opioids are commercially available, but not all are appropriate for the pediatric population. Fentanyl, morphine, and methadone are opioids used in all ages, including neonates.2 Oxycodone and hydromorphone have US Food and Drug Administration–labeled indications for use in those older than 6 months of age. 2Hydrocodone is commonly used off-label for patients younger than 2 years.2,3 The American Pain Society and the Institute for Safe Medication Practices do not recommend meperidine for pediatric analgesic use owing to the accumulation of a toxic metabolite (normeperidine) that may cause central nervous system toxicity, including seizures. This effect is especially significant in patients with renal dysfunction.2,4 The US Food and Drug Administration issued a black box warning for codeine and tramadol in children younger than 12 years and limited use in children between 12 to 18 years of age owing to difficulty breathing and death.5 Oxymorphone is not routinely recommended for use in pediatric patients, as it carries a black box warning for respiratory depression and other warnings regarding the high risk of addiction, abuse, misuse, overdose, and death.2

Concerns for opioid use in the pediatric population also arise from the current opioid epidemic in the United States. A recent study observed that legitimate use of opioids among adolescents before high-school graduation is correlated with a 33% increase in the risk of future non-medical opioid use when reaching young adulthood.6 As of 2015, the rate of opioid misuse among adolescents in the past year and lifetime was 3.9% and 7.8%, respectively, but this rate was much higher (20.1%) in young adults 18 to 29 years of age.7,8 Past month misuse of opioids was reported in 276,000 adolescents, and past year misuse was reported by 17.2% of adolescents who use prescription drugs medically or non-medically in the previous year.7 There are additional concerns for non-medical use of opioids, including a strong association with heroin initiation.9Data from the CDC show that deaths involving heroin among adolescents aged 15 to 19 years increased during the 1999–2015 period and was 3 times higher in 2015 (1.0 per 100,000) than in 1999 (0.3 per 100,000).10 Medication strategies in the home and in practice are essential to curb these trends.Go to:

Recommendations

Pharmacists should educate parents and caregivers on safe administration, storage, and disposal of medications.

Pharmacists should emphasize that medications should not be shared, and caregivers should always give the medication dose prescribed.11 

Storage recommendations should include all medications being out of sight and out of reach of children (e.g., medicine or kitchen cabinet), as well as keeping medications with misuse potential in a more secure location, such as a lock box or medication safe.11,12

In addition, pharmacists should communicate the importance of proper disposal of unused and expired medications in the home in order to reduce the risk of children and adolescents having access to prescription drugs, including opioids.

The Drug Enforcement Administration periodically hosts National Prescription Drug Take-Back events in local communities.13 Additionally, many communities have local drop boxes (www.rxdrugdropbox.org) sponsored by law enforcement for safe disposal of medications.

If a medicine take-back program is unavailable, disposal in the household trash is also appropriate for opioids. Pharmacists should instruct to mix unneeded medications with unpalatable substances, such as kitty litter or used coffee grounds, and place them in a container.

The container with medications should then be thrown in household trash. All personal information on the original prescription bottle should be scratched out, making it unreadable, prior to disposal.

Pharmacists should empower parents and caregivers to talk with children and adolescents about prescription medication misuse and its consequences.11 

Education of prescription drug misuse is a key role for pharmacists to help increase public awareness of misuse dangers.14 

They can also serve as medication experts for families by providing information on the unrecognized risks of opioids, non-opioid options, and guidance on best ways to manage pain.6 

Furthermore, they should be a resource on prevention strategies for parents, schools, and communities including local goverments.1517

Another role of the pharmacist is to review prescription drug–monitoring programs, electronic databases that contain information regarding controlled substance dispensing.18,19 

Because these are maintained at a state level, variation exists as to which medications are monitored, how often reporting is required, and how users can access the system.18 

As recommended by the American College of Physicians and the CDC opioid prescribing guidelines, prescribers should be encouraged to review a patient’s controlled substance history available through prescription drug–monitoring program data.1,20 

Some states have implemented laws regarding patient directives banning the use or offering of opioids to that patient, similar to the concept of a Do Not Resuscitate directive.21

Opioid, or pain management, stewardship is a relatively new concept that involves focusing on optimizing pain management and presents an opportunity for collaborative drug therapy management.

Some hospital systems have developed stewardship programs that focus on inadequate pain management, while others focus on specific opioid medications.22 

Regardless of the existence of formal programs, when prescribing opioids for acute pain, use the smallest possible dose and duration.

For chronic pain, it is important to schedule follow-up assessments and prescribe a quantity that matches future appointments. Pharmacists may also perform universal opioid use screening, brief intervention or motivational interview techniques, and treatment referrals based on clinical assessment.23,24 

Evidence-based treatments including methadone, naltrexone, and buprenorphine for youth with opioid use disorder are available, but underused.17,25 

A recent study found 1 in 4 youth received pharmacotherapy within 6 months of opioid use disorder diagnosis, and the odds for pharmacotherapy were lower in younger, female, and non-Hispanic black and Hispanic patients.26 

Pharmacists can advocate for entry into collaborative practice agreements with licensed prescribers to improve access to pharmacotherapy for detoxification and office-based treatment for adolescents, as well as assist in referrals for care.

When appropriate, pharmacists should advocate for non-opioid pain management options, including nonsteroidal anti-inflammatory drugs, acetaminophen, neuropathic pain options (e.g., pregabalin, duloxetine, lidocaine patch), as well as non-pharmacologic modalities (e.g., biofeedback, acupuncture, distraction techniques), all of which have been extensively described in the literature for numerous subtypes of pain.3 

Non-opioid options could be considered as independent analgesics for specific types of pain or as adjuncts in multimodal therapy to maximize pain relief, since they may enhance opioid analgesic efficacy.

In special pediatric subpopulations, especially hematology and oncology patients, who may require the use of intravenous patient-controlled analgesia, a small dose of naloxone infusion can significantly reduce the incidence and severity of opioid-induced side effects without affecting opioid-induced analgesia.27 

Additionally, coprescribing of intranasal or intramuscular naloxone should be recommended for patients receiving chronic opioid therapy who have a history of overdose, a history of substance use disorder, higher opioid dosages (≥50 morphine mEq/day), or are receiving concurrent benzodiazepines, based on the current CDC opioid guidelines.1 

To increase universal naloxone access, all 50 states have various legislation for non-patient–specific prescriptions, allowing pharmacists to dispense to individuals and organizations without needing to obtain a prescription from a licensed prescriber.28 

The Table presents a summary of these recommendations.

Table.

Recommendations of the Pediatric Pharmacy Advocacy Group for Opioid Use in Children and Adolescents

Pharmacists should proactively engage licensed prescribers on the customized selection of opioids and other non-opioid alternatives.
Pharmacists should actively provide education on proper storage, disposal, and administration of prescription opioids to prevent misuse, overdose, or development of opioid use disorder.
Pharmacists should actively engage in education of patients, families, and local communities to increase public awareness of the dangers regarding opioid misuse.
Pharmacists should lead or actively participate in institutional efforts to implement opioid stewardship programs.
Pharmacists should advocate for universal use of electronic prescription drug–monitoring programs by prescribers and “real-time” data submission of opioids dispensed at pharmacies.
Pharmacists should participate in the distribution of naloxone to individuals and organizations that meet state-determined criteria through standing orders, protocol orders, collaborative practice agreements, or pharmacist prescriptive authority.
Pharmacists should actively endorse the American Academy of Pediatrics policy statement to improve access to evidence-based treatment for adolescents and young adults with opioid use disorder and advocate for an expanded role of the pharmacist in detoxification and office-based pharmacotherapy.

More information: Christopher Eccleston et al, Pharmacological interventions for chronic pain in children, PAIN (2019). DOI: 10.1097/j.pain.0000000000001609

Journal information: Pain
Provided by University of Bath

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