Background

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Under prescribing and undertreating pain for people who have sickle cell disease has been a problem for decades. “Psuedoaddiction” is the term used to describe people living with SCD who are undertreated for pain in the emergency room. Patients are given lower than was previously prescribed pain medication and denied adequate treatment. Pseudoaddiction also encompassed the sharing or giving pain medication to others who had sickle cell disease who were under prescribed, obtaining prescriptions from more than one provider, using then illicit drugs such as marijuana to treat pain.  To most physicians, these are all “red flags” that the person they are treating is addicted to pain medication. This is not the case for people who have SCD, it is due to the chronic undertreatment of pain by providers and to the disparity of medical care for people of color. 

 

Pain does not appear to be very well understood by most providers, it seems difficult for them to distinguish between tolerance, hyperalgesia, allodynia, and addiction.  All are known to occur in people who have severe pain and require pain medication at high doses over days, weeks, or months.  However, they are all physiological side effects with the exception of addiction, which is not more common among people who have SCD as compared to the rest of the population in the United States. 

 

The Centers for Medicare & Medicaid Services, Office of Minority Health (CMM) issued a report on June 19, 2019, considering the implications of the current CDC Guidelines concerning pain prescribing for people who have sickle cell disease.  They compared three covered populations who receive more than the recommended 120 morphine milligram equivalents (MME) per day of pain medication, considered “high dose opioid use” by the Guidelines.  The groups studied were people who have cancer-related pain, people who are in hospice, and people who have sickle cell disease (SCD).  The goal of the report was to inform prescribers on the relative use of pain medication in these groups.

 

 

CDC Guidelines 2016

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The CDC Guideline for Prescribing Opioids for Chronic Pain—United States, 2016 was rapidly adopted by the medical community and was seen as the benchmark of prescribing for all people needing complex prolonged pain management.  These guidelines are helpful for medical providers who are prescribing for the general population, but not for sickle cell disease.  On page 6 of the guidelines, the only recommendation to providers for the treatment of SCD pain is to consult the NIH—NHLBI guidelines for treating sickle cell pain.  There were no recommendations in the guideline for the treatment of SCD and SCD was not excluded from the limitations placed on pain management in the guidelines.  Cancer and end of life care are mentioned in the summary at the beginning of the guidelines and referenced frequently throughout the guidelines as being exempt from the recommendations.

 

 

CDC 2018 Highlight

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This most recent report from the CMM was preceded by a short “Data Highlight” in September of 2018 presenting the data concerning the treatment of sickle cell disease pain and recommending that people who have sickle cell disease be excluded from the current guidelines.  The data from the report was presented as a graph, Figure 1.  Since this initial Data Highlight publication, the authors of the CDC Guidelines have published a Consensus Panel Report in the journal Pain Medicine and written a “Perspective” editorial in the New England Journal of Medicine.  Both were written due to the misinterpretation of the Guidelines by providers.  The consensus report does not address issues with sickle cell disease as the focus is on the general misinterpretation of the guidelines for the general population of individuals who are receiving chronic pain medication for complex pain-related conditions.  The Perspective article does mention sickle cell disease as an exception to the guidelines.

 

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CDC June 2019 Report

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So, what does this most recent report tell the medical community about sickle cell disease and pain management with the title: Opioid Prescription in Medicare Beneficiaries: Prescription Opioid Policies and Implications for Beneficiaries with Sickle Cell Disease.

 

This report should be revealing for those providers not experienced in treating sickle cell disease pain. 

 

• The beneficiaries who have SCD were

  • Younger

  • Primarily African American

  • More likely to have disabilities

  • Living in urban areas

 

This suggested to the CCM what we all know, that people who have SCD have higher vulnerabilities and are less likely to be understood by providers.

 

• The beneficiaries who have SCD have pain-related conditions that are not seen in those who suffer from cancer or are in hospice.

  • Chronic Pain

  • Fatigue

  • Muscular Pain

 

This suggested to the CCM what we all know: people who have SCD have a higher pain-related disease burden and a higher need for chronic pain management than the other groups studied.

 

• People who have SCD are not prescribed greater than 120 MME’s per day more often than other groups with a less severe pain burden.

• People who have SCD face disproportionate challenges compared to others for access to pain medication, consistent with the literature concerning the failure of the medical community to adequately treat people who have SCD for pain.

• Compared to the other groups people who have SCD had LESS outpatient clinic visits, but MORE FREQUENT emergency room use and hospitalization.

 

This suggested to the CMM that the care for SCD is substandard.

 

• People who have sickle cell disease face worse quality of care for pain management with a reliance on high-intensity acute care services for their pain providers and management.

• The hospital admission rate for cancer or hospice patients receiving MME over 120 per day was higher than expected compared to people who have sickle cell disease, who’s admission rate was not related to the dose of pain medication they were receiving.

 

Again, something we all know.  People who have SCD are not admitted more often than other groups who have pain related to their disease.  The quality of care for people who have sickle cell disease is substandard compared to other groups with chronic illness.  This was NOT measured by the study, but we know the substandard care is due to a disparity of care for people of color.

 

• Most people who have sickle cell disease had at least one prescription filled during the study period, the people who had the least prescriptions for pain medication were those who suffered from cancer.

 

• The number of people who had prescriptions for over 120 MME per day where the highest among people who have sickle cell disease.

 

This suggested to the CMM that pain medications are just as important, or more important, for people who have SCD as they are for other people who have chronic pain-related conditions.

 

Again, something we all know.

 

• The number of day’s supply of pain medication for each prescription for those with SCD who required greater than 120 MME’s was less than for cancer or hospice.  The lowest rate for prescriptions of less than 21 days was for SCD.

 

• This indicated that people who have SCD have more issues with transportation to care for their pain and placed a greater burden to have adequate pain management.

• Combined higher refills and shorter duration of prescriptions implies that people who have sickle cell disease have a greater burden than those exempted from restrictions.

 

This burden is much higher than you would expect, not only do people who have sickle cell disease have fewer clinic visits for care, they have more clinic visits just to continue their pain treatment.  What does this mean for people who have sickle cell disease?  They may be receiving most of their prescriptions from emergency room physicians who probably do not prescribe for a longer duration than a week.  Expecting the person who has SCD to have regular visits with their generally nonexistent primary care physician. 

 

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Comment

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This report is more evidence for the health care disparity for those who suffer from sickle cell disease.  This is unacceptable.  With the discontinuation of funding for the Comprehensive Sickle Cell Centers in the United States in 2005 the care for people who have sickle cell disease has declined.  Yes, there are potentially more therapies for SCD coming in the future, but in order to access these therapies, which may be out of reach due to cost, people who have SCD need the same access to medical care as the rest of the population in the United States.  In order to access these therapies, a primary sickle cell physician is necessary.  Assessment and care plans need to be established for patients in order that the new therapies will be appropriate for each individual.  The time for advocacy and action is now.

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This data was collected from the most complete data available, 2016.  The CMM admits that there could have been more people who have SCD in the population of due to misdiagnosis or inaccuracies of coding for SCD, as well as miscoding for the other diseases.  There is no indication as to whether the medication was actually used by the people in the study.  It only included billing to Medicare, if there were other sources of insurance this would not have been included in this study.  Neither does it address the inpatient treatment of pain, the actual level of pain or the pain plans, only the prescription profiles.  However, the CMM felt that prescriptions are a reflection of the degree of pain suffered by people who have SCD due to complications of their disease. 

 

References

 

• CMS Office of Minority Health. Opioid Prescription in Medicare Beneficiaries: Prescription Opioid Policies and Implications for Beneficiaries with Sickle Cell Disease. Baltimore, MD: Centers for Medicare & Medicaid Services; June 2019. https://www.cms.gov/About-CMS/Agency-Information/OMH/Downloads/Opioid-Prescription-in-Medicare-Beneficiaries-Report.pdf

• CDC. (2017b). CDC Guideline for Prescribing Opioids for Chronic Pain. Retrieved from https://www.cdc.gov/drugoverdose/pdf/guidelines_at-a-glance-a.pdf

• CDC. (2018b). CDC Advises Against Misapplication of the Guideline for Prescribing Opioids for Chronic Pain. Retrieved from https://www.cdc.gov/media/releases/2019/s0424-advises- misapplication-guideline-prescribing-opioids.html

• Dowell, D., Haegerich, T., & Chou, R. (2019). No shortcuts to safer opioid prescribing. New England Journal of Medicine, 380(24), 2285-2287. doi: 10.1056/NEJMp1904190

• Haywood, C. Jr., Diener-West, M., Strouse, J., Carroll, C. P., Bediako, S., Lanzkron, S., et al. (2014). Perceived discrimination in health care is associated with a greater burden of pain in sickle cell disease. Journal of Pain and Symptom Management, 48(5), 934-43. doi: 10.1016/j.jpainsymman.2014.02.002.

• Lanzkron, S., Carroll, C. P., & Haywood, C. Jr. (2010). The burden of emergency department use for sickle-cell disease: an analysis of the national emergency department sample database. American Journal of Hematology, 85(10), 797-9. doi: 10.1002/ajh.21807.

• National Institutes of Health (NIH) National Heart, Lung, and Blood Institute. (2014). Evidence-based management of sickle cell disease: Expert panel report, 2014. Retrieved from https://www.nhlbi.nih.gov/health-pro/guidelines/sickle-cell-disease-guidelines

• National Institutes of Health (NIH) National Heart, Lung, and Blood Institute. (2017). Opioid crisis adds to pain of sickle cell patients. Retrieved from https://www.nhlbi.nih.gov/news/spotlight/fact-sheet/opioid- crisis-adds-pain-sickle-cell-patients

(Applies only to research conducted in the United States)

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Sickle cell disease treatment has improved dramatically and the life expectancy of people who have sickle cell disease has been extended due to the research efforts of many people and the willingness of those who have sickle cell disease to participate in this research. 

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THE BASICS
There are many different types of clinical trials and the analysis of the trials can involve complex statistics and protocols, beyond the basics of participation.  Research 101 will address the basic information to help you become an informed participant in research.

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THE INSTITUTIONAL REVIEW BOARD (IRB)
All studies involving humans have to be reviewed by an Institutional Review Board (IRB). There is an IRB in every hospital or clinic that participates in human research; the IRB is composed of people who know about the ethics of research, laypersons, physicians and others who volunteer to review the research conducted in a hospital or clinic.  The IRB is concern is the consent process and whether or not the rights of the subjects are protected, whether the consent process is reasonable, and the consent itself is understandable and complete.  There may or may not be members of the IRB who are knowledgeable about the research study itself.  They rely on the investigators who conduct the research and any published literature to inform them about the study and the study goals. 

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TWO GENERAL CATEGORIES OF STUDIES: Government-Funded and Industry-Funded
Government-funded studies are studies that are funded by governmental agencies and institutions that receive support from the government; the National Institutes of Health (NIH), National Heart, Lung, and Blood Institute (NHLBI), and the Health Resources and Services Administration (HRSA) are three of these government bodies that frequently fund research, there are other sources of government funding for research as well.

 

Government-funded studies are regulated by a the FDA and other bodies with very strict rules as to who and how subjects are selected and in what studies subjects can participate, for example there are specific rules for the participation of children. 

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Industry-funded studies are those that are funded by a pharmaceutical company, a company that makes medical devices, or a company that has developed a new therapeutic intervention such as a new gene therapy or other biologic product or intervention. Generally, these studies are not obligated to follow the government regulations concerning research, but all have to have IRB approval in order to conduct a study in a hospital or clinic.

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If the product or device is seeking approval for use by the Food and Drug Administration (FDA), there must be an investigational new drug or device (IND) authorization from the FDA. The company is then bound by government regulations concerning research.

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PHASES OF A RESEARCH STUDY IN HUMANS
There are three “Phases” of evaluation of a new drug or procedure.

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• Phase I: Researchers test a new drug or treatment in a small group of people for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.

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• Phase II: The drug or treatment is given to a larger group of people to see if it is effective and to further evaluate its safety.

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• Phase III: The drug or treatment is given to large groups of people to confirm its effectiveness, monitor side effects, the drug or treatment may be compared it to commonly used treatments, and to collect information that will allow the drug or treatment to be used safely.

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• Phase IV: Studies are done after the drug or treatment has been marketed to gather information on the drug's effect in various populations and any side effects associated with long-term use.

 

PHASE I STUDIES
This is the first phase of human research following the development of a new treatment, device, biological product, or drug that has never been given to, or used on, humans.  Prior to a Phase I study, there have usually been animal studies with small animals such as mice or in some cases primates, such a monkeys to show that the drug or biologic material is effective in these animal models and is not so toxic as to be life threatening.  

Phase I studies are small studies with a few subjects generating a lot of information.  The participants are the first humans to receive the new treatment or drug.  In some cases, the subjects are paid to participate in these studies.  The goal of a Phase I study is to determine whether the drug or procedure is safe, whether there are side effects that would be serious or life threatening, and at what dose or under what conditions do side effects of the drug or treatment occur.

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Phase I studies are not designed to determine whether the drug or treatment is effective. They are safety studies.  Although in some studies the effectiveness of the drug, biologic, therapy, or device can be inferred from the outcome of the Phase I study.

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Phase I studies can be simple: 
Testing one drug on subjects who are healthy and who have not recently been in other studies would be an example.  The drug or treatment is given in different doses or under different conditions to evaluate which dose is the most effective and whether or not there are side effects at different doses.  There are usually studies of organ function with laboratory testing to be sure there are no adverse effects on the kidney, the muscles, the blood, the chemicals in the blood (metabolic panel), and the endocrine system.  The studies and tests are tailored to what would be expected from the drug or treatment. There are some types of outcome measures decided beforehand.

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Phase I studies can be complex:  
An example would be a new progenitor cell transplant protocol in which drug combinations are new or some of the drugs or processing of the progenitor cells is new, or gene therapy is used as cancer therapy or to change the progenitor cell in some way.  The subjects in this type of study would not be “healthy”; they would have to qualify as having a severe disease that could benefit from such a treatment.  Cancer therapies are common Phase I studies.

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Some studies do not meet the criteria for a Phase I protocol:
A study such as the STOP Study, which used red cell transfusions to see if they could prevent stroke in children with sickle cell disease, would not need to have a Phase I preliminary study as blood transfusions are the standard treatment for people who have had a stroke due to sickle cell disease.  In this case, there were several studies leading up to the STOP Study to show that ultrasound (a procedure already approved for evaluating blood flow in the brain) could predict the possibility of stroke in children who had sickle cell disease.  Once there was evidence that blood flow in the brain could predict stroke, and blood transfusions were already used to decrease stroke recurrence after a stroke, the study could go forward.

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Consent to participate in a study
All studies require informed consent from the subjects.  There are rules about who can consent to studies such as children, people who are incarcerated, people who may not be able to understand the implications of being in a study.  

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In the case of Phase I studies the information for the consent process would be limited as there would be no prior experience with the drug or treatment in humans.  For patients with cancer, it is understandable that participation in a study that could prolong the subjects life and potentially the lives of others would be worthwhile.  Patients with sickle cell disease who are at risk for serious complications such as stroke would also be candidates for Phase I studies that could benefit them and others with the same or similar risk factors.

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Government-funded studies follow government regulations; which state, among other things, that for studies in children the benefit of a Phase I study should outweigh the risks involved.  These requirements would only apply to a government-sponsored study. Otherwise, this requirement may not apply.

 

 

PHASE II STUDIES
A Phase II Study is the second type of study you could be asked to be a part of.  A Phase II Study relies on the information obtained during the Phase I Study to determine whether to proceed to this level of study or not.  Most studies proceed to a Phase II Study if the results in the Phase I Study show the new therapy or procedure is safe in the subjects in the Phase I Study.  

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Unlike the Phase I Study where there is no “control” group, in Phase II Studies there is usually a control group.  A control group consists of subjects who either receive a placebo (usually a pill in a pharmaceutical study that does not contain the active substance, sometimes called a “sugar pill”) or receive the usual standard of care, which is being compared to the new therapy or procedure.

If you enroll in a Phase II Study, you are agreeing that you could be placed in the control group and receive standard care or a placebo.  Since the new therapy is not proven effective, it could be you would do just as well (or sometimes better) in the control group. A recent example of being better off in the control group was a study recently reported in the New England Journal of Medicine to determine what medication would be best for children with migraine headaches.  There were two groups, each receiving a different standard medication for headache and a group receiving no medication (control group).  At the end of the study, it was determined that the medication groups did no better than the control group.  There was a significantly higher rate of side effects in the treatment groups compared to the control group.  The control group actually did as well as the study groups and had fewer side effects.

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Phase II Studies enroll many more people than the Phase I Studies.  In some Phase II Studies, there are hundreds of subjects and the study can last a year or more in order to enroll enough subjects to determine whether the new therapy or procedure is of benefit or equivalent to standard care.  You may be in a Phase II study for up to a year or more.

 

Like all studies enrolling human subjects, the rules for consent are the same as for all other studies.  The difference between a Phase I Study and a Phase II Study is that there is safety information in a Phase II Study that was determined from the Phase I Study.  This allows the study participant to make an informed choice as to whether they feel the study is safe to enroll.  Particularly for parents who are enrolling their children in a study.

 

When you are enrolling in a study, you should understand the significance of the study to advance sickle cell care.  The Penicillin Study (Not a Phase II Study) conducted in 1989 asked parents to enroll their children in a study to determine whether penicillin given twice a day would provide protection to children with sickle cell disease from infection by pneumococcus, the most common cause of death in children who had sickle cell disease. The control group would not receive penicillin.  Would you enroll your child in this study?  

 

It was unknown at the time whether giving penicillin twice a day would protect children from infection.  There were 215 participants in this study.  One hundred and five who were taking penicillin finished the study, 110 who were not taking penicillin finished the study. The study was stopped early, as it was clear that penicillin was protective against infections.  In this study, three children died from infection.  Very sad, but their sacrifice saved the lives of tens of thousands of children who came after them.  At the time of the study in was common that children who were less than five years old to die from infections, their parents were brave to enroll their children and accept being in the control group.  They were truly “sickle cell warriors”.  

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Children with sickle cell disease continue to receive penicillin today thanks to these brave families.  This was a significant study, changing the course of sickle cell disease in the United States.  Prior to the penicillin study, newborn screening was not common.  This study was used as evidence that newborn screening for sickle cell would save lives by identifying infants who should begin taking penicillin by two months of age, preventing 95% of infections by pneumococcus.  

 

 

ENROLLING AND MORE INFORMATION

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When you are enrolling in a study, you should know:

• What are the risks involved in the study?

• Is this a Phase I, Phase II, or Phase III study?

• Is there a control group, what percent of subjects will be in the control group versus the treatment group?

• What is the purpose of the study?

• Why is this study important for children and adults with sickle cell disease?

More Information Online:

• About IRB: http://www.hhs.gov/ohrp/

 

Additional Resource Information on clinical trials can be found at:

• http://clinicaltrials.gov/info/resources

 

Complex, but complete information on the regulations for governmental studies can be found in the Federal Register: 21 CFR 50.52 (and 45 CFR 46.405), 21 CFR 50 subpart D, and 45 CFR 46 subpart D.  

 

These resources can be accessed through government sites or with a search engine on the internet.