Are children with Phelan McDermid syndrome insensitive to pain?

It is not always easy to read David’s expression.

 

The two largest studies of children with 22q13 deletion syndrome (PMS) report that a high tolerance for pain is a very common.  One study reports that 88% of individuals are insensitive to pain based upon medical record review (1) and the other report indicates 77% of individuals are insensitive based on parent reports (2).  Do you believe that?  I have always felt that David tolerates far more pain than most people, but I also had my doubts about how can we really know.  After reading the scientific literature, my doubts are only deeper.  This blog is a quick survey of the literature and what it tells us.  Numbers in parentheses “( )” refer to the scientific studies listed at the end of this blog.

Recently, a group of scientists investigated the pain sensitivity of mice with no Shank3 (complete knockout of both genes) (3). These mice did not have reduced sensitivity to sharp pain. They did have an unusual response to certain types of long-lasting pain. Normally, the skin is more sensitize after certain long lasting pain and mice lacking Shank3 don’t develop as much sensitivity. Like the brain pathways, the spinal cord seems to have deficits, but does this translate to low pain sensitivity in children?

As I reviewed the research literature for pain in children with intellectual disability (ID) and autism spectrum disorder (ASD), a red flag went up immediately.  There is strong evidence that medical practitioners and parents treat most people with ID as if they feel less pain.  This is  not just a problem with PMS.  Children with ID receive less pain medicine after surgery than other children, even though there is no evidence that the side-effects of the medicines are worse for children with ID (4). Parents report that non-communicating children experience painful episodes frequently, yet the parents rarely give these children pain medications (5).  That is not to say parents know less than medical practitioners.  Certain pain scales (which I will discuss in a moment) used in clinical settings are more accurate when parent input is included in the measurement (6). But, parents and medical practitioners seem to think nonverbal children are less pain sensitive. Are they, or do we misunderstand their reactions to pain?

Sensitivity to pain can be objectively studied in several different ways. Luginbuhl et al assessed which methods might provide the most reliable measure of pain (7).  They tested each method with different doses of an analgesic, alfentanil. The idea is, increasing doses of pain medicine should give increasing pain thresholds.  Pain measurements that show less pain with more drug are good ones. Measurements that do not show a consistent reduction of pain with higher doses of drug are poor measures.

The testing was done on normal volunteers: the painful stimulus is gradually increased until the subject either presses a button to stop the stimulator or pulls away from the painful stimulus. The controlled sources of pain were: electrical pain on the toe, pressure pain on the finger, heat pain on the forearm, ice-water pain by immersing the hand, and ischemic pain (tourniquet). In the end, the most reliable tests were electrical pain, pressure pain and ice water. These tests are good measures of pain, right?

Wrong. These tests rely on how quickly the subject reacts to the pain. We can easily misjudge the pain threshold of people with ID because they have slower reaction times. This problem was studied in a group of individuals with Downs syndrome and others with mild ID.  Defrin et al measured pain using two different approaches (8).  One relied on the speed of reacting (Method of limits), and the other did not rely on speed (Method of levels).  Most subjects in this study were verbal, but to make sure, the subjects also pointed to a happy face or sad face to indicate painful or not painful. The results of this study were clear.  The pain threshold of people with ID is very easy to misjudge because of their slower ability to respond.  Even more surprising from this study is that people with ID are more sensitive to pain than control subjects. So, not only were people with ID labeled as being less sensitive to pain, but they were actually more sensitive.

These studies were done with people who had some ability to report pain, but what about people who cannot report pain? The standard practice is to observe the person who is experiencing pain and make a judgement. Is this approach valid?

Symons lead a group wanting to see if trained observers can judge when a nonverbal person is having a sensory experience, and if the observers can identify pain when the experience is painful (9). They tried a simple experiment. Subjects were seated comfortably in a chair. A camera captured 15 seconds of video divided into 3 periods: before, during, and after a stimulus. The stimulus was either a pinprick, warm object, cold object, pressure, or light touch. We assume that at least the pinprick was painful, but we do not know for sure. The camera also recorded 15 second periods with no stimulus at all. The trained observers had to judge whether or not the person was reacting to a stimulus. Reactions were based on the Facial Action Coding System (FACS) and also based on a method by Defrin and colleagues that evaluates head posture (10). The experts were good at deciding which video clips occurred when a stimulus was given. They also found that the 5 second period of stimulus to the skin could be distinguished from the periods just before and just after the stimulus. There was, however, no ability to distinguish pin prick from the other stimuli. So, trained observers can see changes, but it is not clear from this study how well facial expression helps separate painful from non-painful experiences.

A very interesting outcome of this study was the discovery that individuals with self-injurious behavior (SIB) showed greater sensitivity to sensory input than other individuals with ID (9). This is the opposite of what most people expected, and the results have been replicated (11). This is a serious matter and we will return to it later.

Probably the best experimental way to establish a measure of pain in nonverbal subjects with ID is to make measurements when a known pain is present. Two types of known pain have been tested, post-surgical (12), which produces sustained pain, and during a flu shot (10) or blood draw (13), which produces momentary pain. These and similar studies have led to several different measures of pain for clinical settings (14). For example, the Non-Communicating Children’s Pain Checklist (NCCPC-R) and the adult version, the Non-Communicating Adult Pain Checklist (NCAPC) look at reactions to pain: vocalizations, behaviors, facial expressions, body language, flinching/protective actions and physiological reactions (red face, irregular breathing) (15, 16).  They seem to be quite good measures of pain in nonverbal individuals.

The NCCPC has been criticized because it takes 10 minutes to administer, which is too long for clinical settings (14).  The Pediatric Pain Profile (PPP) scale is somewhat faster to administer, but it is still demanding in some settings.  It also requires detailed information from parents/caregivers.  Input from parents/caregivers can be very valuable for improving the accuracy of a pain scale (17).  Unfortunately, even with caregiver input, health practitioners (and likely many others) rely too much on facial expressions when judging pain reaction (13).  Thus, the pain measurement tools are validated (and valuable!), but not simple to use.

In summary, there are objective measures of pain for nonverbal individuals, and young children with ASD or ID, although these measures require careful application to be reliable.  Even verbal individuals with ASD or ID are typically misjudged and often undermedicated.  Painful events are a frequent part of the lives of individuals with PMS.  The belief that children with PMS are less sensitive to pain than other children has not been examined experimentally and, if the story is similar studies of ASD and ID, that belief may be wrong.  If we allow pain to linger, increased pain is not only associated with self-injurious behaviors, but also aggression and stereotypy (11).  We must be very careful about how quickly we judge the potentially painful experiences of our children, and we must let the science help guide our thinking. The alternative may be to subject our children to a lifetime of unnecessary suffering.

 

arm22q13

 

Previous blogs

Looking for Opportunities

Splitting, Lumping and Clustering

Defining Phelan McDermid syndrome

Why don’t we have better drugs for 22q13 deletion syndrome?

What do parents want to know?

Is 22q13 deletion syndrome a mitochondrial disorder?

Educating children with 22q13 deletion syndrome

How to fix SHANK3
Have you ever met a child like mine?
How do I know which genes are missing?

Mouse models
Science Leadership
How can the same deletion have such different consequences?
22q13 and the hope of precision medicine

22q13 Deletion Syndrome: hypotonia

Understanding gene size

Gene deletions versus mutations: sometimes missing a gene is better.

Is 22q13 deletion syndrome a ciliopathy?
Understanding translocations in 22q13 deletion syndrome: genetics and evolution

Understanding deletion size

Can 22q13 deletion syndrome cause ulcerative colitis?

Can 22q13 deletion syndrome cause cancer?

22q13 deletion syndrome – an introduction

 

References

1. Soorya L, Kolevzon A, Zweifach J, Lim T, Dobry Y, Schwartz L, et al. Prospective investigation of autism and genotype-phenotype correlations in 22q13 deletion syndrome and SHANK3 deficiency. Mol Autism. 2013;4(1):18.
2. Sarasua SM, Boccuto L, Sharp JL, Dwivedi A, Chen CF, Rollins JD, et al. Clinical and genomic evaluation of 201 patients with Phelan-McDermid syndrome. Human genetics. 2014;133(7):847-59.
3. Han K, Holder JL, Jr., Schaaf CP, Lu H, Chen H, Kang H, et al. SHANK3 overexpression causes manic-like behaviour with unique pharmacogenetic properties. Nature. 2013;503(7474):72-7.
4. Malviya S, Voepel-Lewis T, Tait AR, Merkel S, Lauer A, Munro H, et al. Pain management in children with and without cognitive impairment following spine fusion surgery. Paediatr Anaesth. 2001;11(4):453-8.
5. Stallard P, Williams L, Lenton S, Velleman R. Pain in cognitively impaired, non-communicating children. Arch Dis Child. 2001;85(6):460-2.
6. Hunt A, Goldman A, Seers K, Crichton N, Mastroyannopoulou K, Moffat V, et al. Clinical validation of the paediatric pain profile. Developmental medicine and child neurology. 2004;46(1):9-18.
7. Luginbuhl M, Schnider TW, Petersen-Felix S, Arendt-Nielsen L, Zbinden AM. Comparison of five experimental pain tests to measure analgesic effects of alfentanil. Anesthesiology. 2001;95(1):22-9.
8. Defrin R, Pick CG, Peretz C, Carmeli E. A quantitative somatosensory testing of pain threshold in individuals with mental retardation. Pain. 2004;108(1-2):58-66.
9. Symons FJ, Harper V, Shinde SK, Clary J, Bodfish JW. Evaluating a sham-controlled sensory-testing protocol for nonverbal adults with neurodevelopmental disorders: self-injury and gender effects. J Pain. 2010;11(8):773-81.
10. Defrin R, Lotan M, Pick CG. The evaluation of acute pain in individuals with cognitive impairment: a differential effect of the level of impairment. Pain. 2006;124(3):312-20.
11. Courtemanche AB, Black WR, Reese RM. The Relationship Between Pain, Self-Injury, and Other Problem Behaviors in Young Children With Autism and Other Developmental Disabilities. Am J Intellect Dev Disabil. 2016;121(3):194-203.
12. Breau LM, Finley GA, McGrath PJ, Camfield CS. Validation of the Non-communicating Children’s Pain Checklist-Postoperative Version. Anesthesiology. 2002;96(3):528-35.
13. Messmer RL, Nader R, Craig KD. Brief report: judging pain intensity in children with autism undergoing venepuncture: the influence of facial activity. J Autism Dev Disord. 2008;38(7):1391-4.
14. Crosta QR, Ward TM, Walker AJ, Peters LM. A review of pain measures for hospitalized children with cognitive impairment. J Spec Pediatr Nurs. 2014;19(2):109-18.
15. Lotan M, Ljunggren EA, Johnsen TB, Defrin R, Pick CG, Strand LI. A modified version of the non-communicating children pain checklist-revised, adapted to adults with intellectual and developmental disabilities: sensitivity to pain and internal consistency. J Pain. 2009;10(4):398-407.
16. Lotan M, Moe-Nilssen R, Ljunggren AE, Strand LI. Measurement properties of the Non-Communicating Adult Pain Checklist (NCAPC): a pain scale for adults with Intellectual and Developmental Disabilities, scored in a clinical setting. Res Dev Disabil. 2010;31(2):367-75.
17. Malviya S, Voepel-Lewis T, Burke C, Merkel S, Tait AR. The revised FLACC observational pain tool: improved reliability and validity for pain assessment in children with cognitive impairment. Paediatr Anaesth. 2006;16(3):258-65.