While the inability to feel any kind of pain may seem like a superhuman power, those that suffer

from
insensitivity to pain, or congenital analgesia, understand that the dangers it poses are all too real. In the human
body, nerves allow us to physically interact with the world. They can be pictured as car headlights - without
which, we drive along blindly, not knowing something is crashing into us until the actual crash. When a young
child hits their head on a table, they feel pain, and cry. This both alerts those in the vicinity that the child may be
in serious pain, as well as teaches the child that hitting their head is not a good thing. However, when the child
feels no pain, and merely gets back up again and continues to run around, they do not learn of the dangers of
hitting their head on the table, and can suffer much more damage later on. The threat that congenital analgesia
causes to the lives of those living with it is significant. There are many life threatening maladies that we are
made aware of through pain. Prior to the appendix rupturing, individuals feel an intense pain which can alert
them to contact their doctor. Without the ability to feel pain, there is nothing they can do to predict their
appendix rupturing, which usually results in death.

While there is no drug capable of curing congenital analgesia completely, because of the huge variety of
causes, there are drugs that are currently in circulation that can be adapted very easily to cure congenital
insensitivity to pain. One very viable drug is Naloxone, which is currently a highly effective overdose reversal
drug, designed to unclog sodium channels which can inhibit sensory impulses. With Naloxone, the serious
threat of congenital analgesia can be heavily mitigated, and can pave the way for development of even more
refined drugs to combat other forms of congenital analgesia.

Congenital analgesia, often referred to as congenital insensitivity to pain, is a very unique condition, given
its very different manifestations and causes. Some people are born with it while others acquire it through
various means, and the degrees of insensitivity are very different. [1]

The condition itself remains largely consistent among all of the examined subjects within scientific
literature - the lack of the ability to feel pain.

Individuals who suffer from this condition often end up having to amputate limbs due to broken bones or
fractures not being detected until they become infected or permanently damage the limb, as well as
usually don't live for a very long time, because the conditions that cause CIP, in many cases, result from
drug abuse or third world conditions, both of which probably indicate individuals who aren't likely to attend
hospitals for daily checkups. [1]

To find more information about the variances of the disease, these resources are available to the public:

MedlinePlus - Health information (3 links)
Additional NIH Resources - National Institutes of Health
National Institute of Neurological Disorders and Stroke: Peripheral Neuropathy Information Page
Educational resources - Information pages (7 links)
Patient support - For patients and families
The Neuropathy Association

You may also be interested in these resources, which are designed for healthcare professionals and
researchers.
Genetic Testing Registry - Repository of genetic test information (1 link)
PubMed - Recent literature
OMIM - Genetic disorder catalog

|| History of Naloxone||
Naloxone was developed in 1960 as a response to the growing need of an actual opioid antagonist, as opposed to its
predecessor, nalorphine (a derivative of morphine) which was only a partial antagonist. It was developed by the
Japanese country, Sankyo. An interesting fact about Naloxone is that it is highly specific and very accurate if there
are no opioids in the body, then it has no pharmacological effects whatsoever. In fact, there are developments being
made that would permit non-medically trained people from making Naloxone a take-home drug, but the small link
to pulmonary failure which, although probably not related to Naloxone, still poses a risk factor. Some other side
effects of using Naloxone, especially in drug overdosage patients, are the immediate effects of a withdrawal. Since
2002, the FDA has permitted the use of buprenorphine to be taken to mitigate the effects of the withdrawal
symptoms, but the combination is still risky, since there are chances that buprenorphine causes the withdrawal
symptoms as well. [2]
|| How Naloxone Works ||
Naloxone has been adapted from use in alleviating the effects of drug overdosing to potentially curing some forms
of CIP, because the two have very similar results. In a drug overdose, certain sodium channels become clogged
because of the massive amount of endorphins being released. Naloxone helps unclog those channels by functioning
as an opioid antagonist, and stimulating them to move out of the channel, allowing a more normal flow. In some
cases of CIP, specifically related to drug overdoses, Naloxone can operate in the same way, by unclogging those
channels. [4]
In a normal system, opioid agents/endorphins bind to protein receptors to inhibit pain. These effects occur naturally,
but can also be the result of specific drugs, such as morphine. These endorphins are released via the peripheral
nervous system, and produce analgesia which causes the inhibition of tachykinins.[1]
This endorphine overdose blocks the channels in the brain cell. The blockage prevents pain signals from being
transmitted.


Figure 1 - a normal pathway versus endorphin blocked pathway
A linked mutation in the SCN9A gene can be traced to the NaV1.7 sodium gated ion channel, which is an alternate
cause of the prevention of a pain signal, but is not treatable by Naloxone (shown below).[2]



In this diagram, Narcan [Naloxone] is demonstrated to inhibit the blockage of receptors of endorphins/opioids by
demonstrating a stronger affinity. This is only occasionally effective, because a) the cause of CIP is indeterminate,
as there are multiple links, and b) tests have demonstrated that Naloxone is only sometimes strong enough to
overcome the blockages that exist in CIP.[2]

The study examined how Naloxone interacts in body systems, as well as what are the possible side
effects. Naloxone, an opioid antagonist, specifically blocks the u-opioid receptors, which reverses the effects of
opioid overdoses. [2] Naloxone is also uniquely effective because of its low intrinsic efficacy, which means that it
does not work in a normal, healthy system. Studies like the one conducted by Handal et al demonstrate that the
pharmacological effects of Naloxone differ in patients with and without opioid dependence based on a 30%
difference in plasma concentration of Naloxone. This increases its viability because it reduces the chances for
improper use of Naloxone, accidental or otherwise. This constitutes it as a safe drug, which is beginning to be
advocated for use at home, since its effectiveness would be much more utilized immediately when the overdose
occurs, rather than at the hospital, which would be much later after the original opioid stimulation. On the other
hand, while this rapid administration may cause a more rapid reversal, it can also have much greater side effects,
such as cardiac arrhythmias. However, there can be health problems when Naloxone is consumed with an opioid
overdose even later, since it can immediately begin acute withdrawal symptoms, which can manifest themselves for
up to several weeks. This complex combination of side effects must be balanced by the original opioid overdose
itself, and thus is the main reason why the drug has not been approved to be taken by individuals at home, rather
than in the hospital. [2]
Naloxones effectiveness in treating opioid induced problems is varied based on the opioid stimulation. For example,
while its simple and efficient interactions with morphine induced overdoses lead to a reversal of symptoms within a
few minutes, the more complex interactions it has with buprenorphine make the reversal time much longer.
Additionally, the efficacy changes based on how Naloxone is placed into the system, whether orally, intravenously,
or other methods. A common method used to mediate the effects of Naloxone, regardless of how it is ingested, is to
accompany it with doses of agonists like methadone or buprenorphine, which mitigate the symptoms of withdrawal.
Another technique is to sedate the individual when administering Naloxone, to prevent the effects from displaying.
Some main problems that exist in the use of Naloxone are its low availability, as well as extremely rapid action time.
This means that while it is a good solution in a pressured situation, where a patient must be stabilized, it cannot be
used as the sole cure for any opioid overdose, since there isnt enough of it to consistently give every patient a
dosage, as well as the reaction time makes it undesirable to be administered consistently over long periods, at the
vastly increased chance of side effects. Furthermore, it cannot be utilized as an abstinence agent, simply because it
reacts too quickly to be used over long periods of time effectively. [2]
Naloxone itself is an extremely adaptable drug. The targeting of opioid receptors makes it extremely viable in
treating all kinds of health problems related to these receptors. Applications are not limited to the reversal of the
effects of CIP, if it indeed is caused by opioid receptors being overstimulated. Being such a flexible drug, Naloxone
has a vast amount of potential to reverse a variety of opioid related problems.
Table 6.1: Use and side effects of naloxone in opioid-dependent
individuals

Naloxone
Use
Side effects .
Opioid overdose
Acute withdrawal
symptoms

Detoxification
Recurrence of
respiratory
depression

Maintenance
Cardiac
arrhythmias,
pulmonary edema




In the past, drugs used to treat opioid addiction have been both time consuming and extremely uncomfortable for the
patient to use. Thus, the development of a drug that was able to act as an opioid antagonist in a more efficient
manner was required. The development of Naloxone to treat various kinds of opioid problems has a few side effects.
The table compares the use to the possible side effects. In detoxification, Naloxone can cause acute withdrawal
system, in detoxification, it can cause recurrence of respiratory depression, and in maintenance, it can cause
pulmonary edema and cardiac arrhythmias. [2] This table is significant because it gives context in the possible
problems with making Naloxone a take home drug, capable of being taken without a doctor supervising. In
patients with CIP, the causes and cures are extremely varied, and thus diagnosis may be incorrect. However,
Naloxone accounts for this by having no side effects from consumption if the diagnosis is wrong. But, if the problem
is indeed an overdosage of opioids, then the problems highlighted in the table may be riskier side effects.



1. "Naloxone." Official FDA Information, Side Effects and Uses. N.p., n.d. Web. 13 Mar. 2014.
2. Van Dorp, E. 2007. Naloxone treatment in opioid addiction: the risks and the benefits. Expert Opin. Drug Saf. (2007) 6(2):
125-132. Available from Open Access/Leid University.
3. Sprouse-Blum, A. 2010. Understanding Endorphins and their Importance in Pain Management. Hawaii Med J. Mar
2010; 69(3): 7071. Available from: PMC/PMC3104618
4. "Narcan (Naloxone) Drug Information: Clinical Pharmacology - Prescribing Information at RxList." RxList. N.p., n.d.
Web. 13 Mar. 2014.


Images
5. News, ABC. GIrl Suffering from Congenital Analgesia. 2001.
6. Van Dorp, E. Effects of Narcan. 2004.
7. Federal Health Website. Endorphin pathway. 2012.
8. Frontiers. Sodium NaV1.7 channel. 2011.