Category: Pain Management

Categories : Addiction Pain ManagementTags :

Dependence on Pain Medication is on the Rise

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Dependence on pain medication is on the rise due to lack of vigilance by medical professionals, according to a new study from the University of Surrey. In the paper published in the journal Pain and Therapy, patients dependent on pain medication describe feelings of ‘living in a haze’ and being ignored and misunderstood by the medical profession.

In the first study of its kind in the UK, Louise Norton and Dr Bridget Dibb from the University of Surrey investigated the experiences of patients dependent on medication for chronic pain. Pharmacological treatment for chronic pain usually involves potentially addictive substances such as non-steroidal anti-inflammatory drugs, gabapentinoids, and opioids. Increased prescription levels of such pain relief medications have been associated with heightened levels of overdose and misuse.

Dr Bridget Dibb, Senior Lecturer in Health Psychology at the University of Surrey, said: “An increasing number of people are experiencing chronic pain, which can interfere with their daily life and lead to depression and anxiety. Medication can help alleviate pain and return a sense of normalcy to a person’s life; however, there is a risk of dependence, which can potentially cause damage to vital organs, including the liver and kidneys.

“The first step to tackle this problem is to learn more about a person’s experience, how they perceive their dependence and how they interact with others, including the medical profession.”

To learn more, interviews were carried out with nine participants who had become dependent on pain medication. Participants spoke about how their dependence on pain medication resulted in them feeling not fully present and removed from their lives due to the side effects of the treatment. Many also expressed frustration about the lack of alternative treatment options available on the NHS to manage their pain, with medications being too readily prescribed.

The majority of participants also spoke about their negative interactions with medical professionals, with some attributing the cause of their dependence on them. Many believed a lack of continuity between doctors led to missed opportunities in spotting their dependence, enabling it to continue.

Louise Norton added: “Relationships with medical professionals substantially affect the experiences of those with painkiller dependence. Doctors can often be seen as authority figures due to their expertise and so patients may be apprehensive to question their treatment options. However, through providing patients with thorough information, doctors can enable more shared-decision making in which patients feel better supported and equipped to manage their chronic pain.”

Researchers noted participants felt stigmatised when speaking with others about their dependence due to a lack of understanding about their reliance to prescribed pain medications. Such interactions left participants feeling ashamed and critical of themselves.

Dr Dibb added: “Those with a dependence on prescription painkillers not only have to navigate their reliance on the medication but the shame and guilt associated with such a need. Combining this with feelings of being misunderstood and ignored by medical professionals, they have a lot of emotional needs to be managed alongside their physical pain. To prevent this from happening medical professionals need to be more vigilant when prescribing medication and ensure that their patients are fully aware of the risk of dependence before they begin treatment.”

Source: University of Surrey

Categories : New Compounds and Treatments Pain ManagementTags :

New Compound Outperforms Gabapentin for Pain Relief

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A new compound reversed four types of chronic pain in animal studies, according to new research published online in the Proceedings of the National Academy of Sciences (PNAS). It outperformed gabapentin without troublesome side effects, providing a promising candidate for treating pain.

Researchers led by NYU College of Dentistry’s Pain Research Center developed this small molecule, which binds to an inner region of a calcium channel to indirectly regulate it.

Calcium channels play a central role in pain signaling, in part through the release of neurotransmitters such as glutamate and GABA – “the currency of the pain signal,” according to Rajesh Khanna, director of the NYU Pain Research Center and professor of molecular pathobiology. The Cav2.2 (or N-type) calcium channel is the target for three clinically available drugs, including gabapentin and pregabalin, which are widely used to treat nerve pain and epilepsy.

Gabapentin mitigates pain by binding to the outside of the Cav2.2 calcium channel, affecting the channel’s activity. However, like many pain medications, gabapentin use often comes with side effects.

“Developing effective pain management with minimal side effects is crucial, but creating new therapies has been challenging,” said Khanna, the senior author of the PNAS study. “Rather than directly going after known targets for pain relief, our lab is focused on indirectly targeting proteins that are involved in pain.”

Inside the channel

Khanna has long been interested in a protein called CRMP2, a key regulator of the Cav2.2 calcium channel that binds to the channel from the inside. He and his colleagues previously discovered a peptide derived from CRMP2 that could uncouple CRMP2 from the calcium channel. When this peptide – calcium channel-binding domain 3 (CBD3) – was delivered to cells, it acted as a decoy, blocking CRMP2 from binding to the inside of the calcium channel. This resulted in less calcium entering the calcium channel and less neurotransmitter release, which translated to less pain in animal studies.

Peptides are difficult to synthesise as drugs because they are short-acting and easily degrade in the stomach, so the researchers sought to create a small molecule drug based on CBD3. Starting with the 15 amino acids that make up the CBD3 peptide, they honed in on two amino acids that studies showed were responsible for inhibiting calcium influx and mitigating pain.

“At that point, we realised that these two amino acids could be the building blocks for designing a small molecule,” said Khanna.

From 27 million to one

In collaboration with colleagues at the University of Pittsburgh, the researchers ran a computer simulation that screened a library of 27 million compounds to look for a small molecule that would “match” the CBD3 amino acids.

The simulation narrowed the library down to 77 compounds, which the researchers experimentally tested to see if they lessened the amount of calcium influx. This further pared the pool down to nine compounds, which were assessed using electrophysiology to measure decreases in electrical currents through the calcium channels.

One compound, which the researchers named CBD3063, emerged as the most promising candidate for treating pain. Biochemical tests revealed that CBD3063 disrupted the interaction between the CaV2.2 calcium channel and CRMP2 protein, reduced calcium entering the channel, and lessened the release of neurotransmitters.

“Many scientists have screened the same library of compounds, but have been trying to block the calcium channel from the outside. Our target, these two amino acids from CRMP2, is on the inside of the cell, and this indirect approach may be the key to our success,” said Khanna.

Four labs, four types of pain

Khanna’s lab then tested CBD3063 with mouse models for pain related to injury. The compound was effective in alleviating pain in both male and female mice – and notably, in a head-to-head test with the drug gabapentin, the researchers needed to use far less CBD3063 (1–10mg) than gabapentin (30 mg) to reduce pain.

To explore whether CBD3063 helped with different types of chronic pain, Khanna partnered with researchers at Virginia Commonwealth University, Michigan State University, and Rutgers University. Collaborators ran similar studies administering CBD3063 to treat animal models of chemotherapy-induced neuropathy, inflammatory pain, and trigeminal nerve pain – all successfully reversing pain, similar to gabapentin.

But unlike gabapentin, the use of CBD3063 did not come with side effects, including sedation, changes to cognition such as memory and learning, or changes to heart rate and breathing.

What’s next

The researchers are continuing to study CBD3063, refining its chemical composition and running additional tests to study the compound’s safety and assess if tolerance develops.

Long-term, they hope to bring a CBD3063-derived drug to clinical trials in an effort to offer new options for safe and effective pain relief.

“Identifying this first-in-class small molecule has been the culmination of more than 15 years of research. Though our research journey continues, we aspire to present a superior successor to gabapentin for the effective management of chronic pain,” said Khanna.

Source: New York University

Categories : Cardiovascular Disease Pain ManagementTags :

Only 30% of Adults Discuss OTC Pain Relievers with Doctors Despite Hypertension Risk

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Only about 30% of US adults have spoken with their health care professional about the adverse effects some over-the-counter (OTC) pain relievers can have on blood pressure. The findings are part of a recent online poll commissioned by the American Heart Association.

Some pain relievers may raise blood pressure, according to the American Heart Association’s most recent Guideline for the Prevention, Detection, Evaluation and Management of High Blood Pressure. 

“It’s paramount that people who have high blood pressure, or are at risk for it, understand the effects associated with some over-the-counter pain relievers,” said Mitchell S. V. Elkind, MD, MS, FAHA, chief clinical science officer of the American Heart Association and a tenured professor of neurology and epidemiology at Columbia University. “A conversation with a health care professional about pain relief options is essential to preventing and managing high blood pressure.”

High blood pressure affects almost half of all people in the US. According to the American Heart Association’s recent poll, of those who have been diagnosed with high blood pressure, white and Asian adults (40%) are significantly less likely than Black (54.2%) and Hispanic (54.1%) adults to have ever discussed the effect some pain relievers have on blood pressure with a health care professional.
“Some over-the-counter pain relievers are safer than others,” added Elkind. “A conversation with a health care professional regularly about medications you or a loved one takes is an important step in finding safe options and controlling blood pressure.”

The poll conducted by Big Village, a collaborative and consultative research firm, also looked at how often people used OTC pain relievers. Of the close to 3000 US adults aged 18 and older surveyed, nearly 50% took medication for pain once a week or more. Adults aged 45-54 take them most frequently of all age groups polled. Additional findings include:

  • Gen X, people born from 1965 to 1980, are significantly more likely than other generations to take OTC pain relievers multiple times a day, but only 41% of Gen X would initially ask a health care professional for alternative pain relief even if they knew some OTC pain relievers can raise a person’s blood pressure.
  • Gen Z, people born from 1997 to 2012, are significantly less likely (30.5%) than any other generation to initially ask their health care professional for alternative pain relief if they knew some OTC pain relievers can raise a person’s blood pressure.
  • 61% of all respondents had not discussed the effect some over-the-counter pain relievers have on blood pressure with a health care professional.
  • 22% would research an alternative pain reliever online, second only to discussing with a health care professional.

Source: American Heart Association

Categories : Neurology Pain ManagementTags :

How Sleep Disruption Can Make Pain Feel Worse

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People often experience headaches and body pain after a lack of sleep, but the mechanisms behind this phenomenon are unclear. A new study published in Nature Communications reveals that a certain endocannabinoid neurotransmitter plays a major role.

The animal-based study, led by investigators at Massachusetts General Hospital (MGH), a founding member of Mass General Brigham (MGB), found that the heightened pain sensitivity than can result from chronic sleep disruption (CSD) – or CSD-induced hyperalgaesia – involved signalling from a part of a brain known as the thalamic reticular nucleus (TRN).

Analyses of metabolites showed that the level of N-arachidonoyl dopamine (NADA), a type of neurotransmitter called an endocannabinoid, decreased in the TRN as a result of sleep deprivation.

Activity of the cannabinoid receptor 1, which is involved in controlling pain perception, also decreased in the thalamic reticular nucleus after CSD.

Administering NADA to the TRN reduced CSD-induced hyperalgaesia in mice.

This beneficial effect of administered NADA could be countered by blocking the cannabinoid receptor 1, suggesting that both the receptor and NADA play a role in pain sensitivity due to sleep deprivation.

“We provide a mechanism as to how sleep disruption leads to exaggerated pain, suggesting that harnessing the endocannabinoid system might break the vicious cycle between pain and sleep loss,” says co-senior author Shiqian Shen, MD, the clinical director of MGH’s Tele Pain Program.

Source: Massachusetts General Hospital

Categories : Pain Management Surgeries & ProceduresTags :

No Increase in Post-surgical Pain Seen with Opioid Limits

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Concerns that surgery patients would have a more difficult recovery if their doctors had to abide by a five-day limit on opioid pain medication prescriptions did not play out as expected, finds a study published in JAMA Health Forum.

Instead, the University of Michigan-led researchers found that , after the largest insurer in that US state put the limit in place, patient-reported pain levels and satisfaction didn’t change at all for adults who had their appendix or gallbladder removed, a hernia repaired, a hysterectomy or other common operations.

At the same time, the amount of opioid pain medication patients covered by that insurer received dropped immediately after the limit went into effect. On average, patients having these operations received about three fewer opioid-containing pills.

The study, which merges two statewide databases on patients covered by Blue Cross Blue Shield of Michigan, is the first large study to evaluate whether opioid prescribing limits change patient experience after surgery.

Measuring the impact of limits from patients’ perspectives

The BCBSM limit of five days’ supply, which went into effect in early 2018, is even stricter than the seven-days’ supply limit put in place a few months later by the state of Michigan.

Other major insurers and states have also implemented limits, most of which allow are seven-day limits.

Limits are designed to reduce the risk of long-term opioid use and opioid use disorder, as well as to reduce the risk of accidental overdose and the risk of unauthorized use of leftover pills.

“Opioid prescribing limits are now everywhere, so understanding their effects is crucial,” said lead author Kao-Ping Chua, MD, PhD.

“We know these limits can reduce opioid prescribing, but it hasn’t been clear until now whether they can do so without worsening patient experience.”

He noted that even the 15% of patients who had been taking opioids for other reasons before having their operations showed neither an increase in pain nor a decrease in satisfaction after the limit was put in place, even though opioid prescribing for these patients decreased.

That decrease was actually contrary to the intent of the limit, which was only designed to reduce prescribing to patients who hadn’t taken opioids recently.

How the study was done

For the new study, Chua and colleagues used data from the Michigan Surgical Quality Collaborative, which collects data on patients having common operations at 70 Michigan hospitals. The MSQC surveys patients about their pain, level of satisfaction and level of regret after their operations.

The team paired anonymized MSQC data with data on controlled substance prescription fills from Michigan state’s prescription drug monitoring programme, called MAPS.

In all, they were able to look at opioid prescribing and patient experience data from 1,323 BCBSM patients who had common operations in the 13 months before the five-day limit went into effect, and 4,722 patients who had operations in the 20 months after the limit went into effect.

About 86% of both groups were non-Hispanic white, patients’ average age was just under 49,  and just under a quarter of both groups had their operations on an emergency or urgent basis. Just under half were admitted to the hospital for at least one night.

About 27% of both groups had their gallbladders taken out laparoscopically, and a similar percentage had minor hernia repairs.

About 10% had an appendectomy done laparoscopically, and a similar percentage had laparoscopic hysterectomies.

The rest had more invasive procedures, like open hysterectomies major hernia repairs, or colon removal. 

The percentage of prescribers who prescribed opioids to their patients having these operations did not change, but the percentage of patients who filled a prescription for an opioid did, possibly because pharmacists rejected prescriptions that weren’t compliant with the BCBSM limit, Chua speculates.

Jennifer Waljee, MD, MPH, MS, senior author of the study, notes that the MSQC database doesn’t include all types of procedures, such as knee replacements and spine surgery, which typically require larger postoperative opioid prescriptions because of their associated pain.

She indicated that it’s important to understand the impact of opioid prescribing limits on the experiences of such patients, because limits have the most potential to worsen pain for these individuals. 

“Opioid prescribing limits may not worsen patient experience for common, less-invasive procedures like those we studied, because opioid prescriptions for most of these procedures were already under the maximum allowed by limits.

“But this may not be the case for painful operations where opioid prescribing was suddenly cut from an 8- to 10-day supply to a 5-day supply,” said Waljee.

She added, “The message of this study is not that we can simply go to five days’ supply across the board for operations.

“We need to understand the effects of these limits across a broad range of procedures and patients given how much pain needs vary in order to right size prescribing to patient need without resulting in additional harms.”

Source: University of Michigan

Categories : Genetics Pain ManagementTags :

Neanderthal Gene Variants Associated with Greater Sensitivity to Some Types of Pain

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People who carry three gene variants that have bene inherited from Neanderthals are more sensitive to some types of pain, according to a new study co-led by UCL researchers. The findings, published in Communications Biology, are the latest findings to show how past interbreeding with Neanderthals has influenced the genetics of modern humans.

The researchers found that people carrying three so-called Neanderthal variants in the gene SCN9A, which is implicated in sensory neurons, are more sensitive to pain from skin pricking after prior exposure to mustard oil.

Previous research has identified three variations in the SCN9A gene – known as M932L, V991L, and D1908G – in sequenced Neanderthal genomes and reports of greater pain sensitivity among humans carrying all three variants. However, prior to this study the specific sensory responses affected by these variants was unclear.

An international team measured the pain thresholds of 1963 people from Colombia in response to a range of stimuli.

The SCN9A gene encodes a sodium channel that is expressed at high levels in sensory neurons that detect signals from damaged tissue. The researchers found that the D1908G variant of the gene was present in around 20% of chromosomes within this population and around 30% of chromosomes carrying this variant also carried the M932L and V991L variants.

The authors found that the three variants were associated with a lower pain threshold in response to skin pricking after prior exposure to mustard oil, but not in response to heat or pressure. Additionally, carrying all three variants was associated with greater pain sensitivity than carrying only one.

When they analysed the genomic region including SCN9A using genetic data from 5971 people from Brazil, Chile, Colombia, Mexico and Peru, the authors found that the three Neanderthal variants were more common in populations with higher proportions of Native American ancestry, such as the Peruvian population, in which the average proportion of Native American ancestry was 66%.

The authors propose that the Neanderthal variants may sensitise sensory neurons by altering the threshold at which a nerve impulse is generated. They speculate that the variants may be more common in populations with higher proportions of Native American ancestry as a result of random chance and population bottlenecks that occurred during the initial occupation of the Americas. Although acute pain can moderate behaviour and prevent further injury, the scientists that say additional research is needed to determine whether carrying these variants and having greater pain sensitivity may have been advantageous during human evolution.

Diagram comparing the nose shape of a Neanderthal with that of a modern human by Dr Macarena Fuentes-Guajardo.

Previous research by co-corresponding author Dr Kaustubh Adhikari (UCL Genetics, Evolution & Environment and The Open University) has shown that humans also inherited some genetic material from Neanderthals affecting the shape of our noses.

Dr Adhikari commented: “In the last 15 years, since the Neanderthal genome was first sequenced, we have been learning more and more about what we have inherited from them as a result of interbreeding tens of thousands of years ago.

“Pain sensitivity is an important survival trait that enables us to avoid painful things that could cause us serious harm. Our findings suggest that Neanderthals may have been more sensitive to certain types of pain, but further research is needed for us to understand why that is the case, and whether these specific genetic variants were evolutionarily advantageous.”

First author Dr Pierre Faux (Aix-Marseille University and University of Toulouse) said: “We have shown how variation in our genetic code can alter how we perceive pain, including genes that modern humans acquired from the Neanderthals. But genes are just one of many factors, including environment, past experience, and psychological factors, which influence pain.”

Source: University College London

Categories : COVID Pain ManagementTags :

Does COVID Infection or Vaccination Worsen Migraines?

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Headaches are a frequent complaint of those with a COVID infection, or have received a COVID vaccination, and it is thought that it may subsequently increase the frequency of migraines. To put this to the test, an observational study published in the European Journal of Neurology investigated the effects on migraine frequency of having had either been infected with COVID or having received a COVID vaccination.

Among 550 adults who had received migraine-related care at a Spanish headache clinic, 44.9% (247) reported COVID at least once and 83.3% (458) had been vaccinated; 61 patients (24.7%) reported migraine worsening since COVID and 52 (11.4%) since vaccination.

In participants who perceived that their migraines worsened, those who had been infected were 2.5-times more likely to be concerned about migraine worsening and patients who had been vaccinated were 17.3-times more likely to have this concern.

When investigators examined patients’ e-diary information, they observed no significant difference in headache frequency one month before and after infection or vaccination, even when comparing patients with and without self-reported migraine worsening.

“In the case of COVID-19, we reported previously that indeed headache is a frequent and disabling symptom of the infection; yet, it may not necessarily be linked to an increase in migraine frequency,” the authors wrote. “In light of our results, we believe that clinicians should deliver to patients a more reassuring message that COVID-19 and COVID-19 vaccines may marginally affect migraine course and that probably the impact of the infection and vaccines is less than the individual rhythmicity to have attacks. This information may help minimise their worry.”

Source: Wiley

Categories : Pain ManagementTags :

Chronic Back Pain may be Easier to Treat if it’s ‘in the Brain’

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One therapy for chronic back pain is to teach patients how to ‘reprocess’ it in the brain. Now, this therapy may become even more effective thanks a study published in JAMA Network Open. The study examined the critical connection between the brain and pain for treating chronic pain. Specifically, they looked at the importance of pain attributions, which are people’s beliefs about the underlying causes of their pain, to reduce chronic back pain severity. Understanding the source of the pain may help some to avoid surgery which may be ineffective or even worsen the pain.

“Millions of people are experiencing chronic pain and many haven’t found ways to help with the pain, making it clear that something is missing in the way we’re diagnosing and treating people,” said the study’s first author Yoni Ashar, PhD, assistant professor of internal medicine at the University of Colorado Anschutz Medical Campus.

Pain is often in the brain

Ashar and his team tested whether the reattribution of pain to mind or brain processes was associated with pain relief in pain reprocessing therapy (PRT), which teaches people to perceive pain signals sent to the brain as less threatening. Their goal was to better understand how people recovered from chronic back pain. The study revealed after PRT, patients reported reduced back pain intensity.

“Our study shows that discussing pain attributions with patients and helping them understand that pain is often ‘in the brain’ can help reduce it,” Ashar said.

To study the effects of pain attributions, they enrolled over 150 adults experiencing moderately severe chronic back pain in a randomised trial to receive PRT. They found that two-thirds of people treated with PRT reported being pain-free or nearly so after treatment, compared to only 20% of placebo controls.

“This study is critically important because patients’ pain attributions are often inaccurate. We found that very few people believed their brains had anything to do with their pain. This can be unhelpful and hurtful when it comes to planning for recovery since pain attributions guide major treatment decisions, such as whether to get surgery or psychological treatment,” said Ashar.

Before PRT treatment, only 10% of participants’ attributions of PRT treatment were mind- or brain-related. However, after PRT, this increased to 51%. The study revealed that the more participants shifted to viewing their pain as due to mind or brain processes, the greater the reduction in chronic back pain intensity they reported.

The role of discussing brain drivers of chronic pain 

“These results show that shifting perspectives about the brain’s role in chronic pain can allow patients to experience better results and outcomes,” Ashar adds.

Ashar says that one reason for this may be that when patients understand their pain as due to brain processes, they learn that there is nothing wrong with their body and that the pain is a ‘false alarm’ being generated by the brain that they don’t need to be afraid of.

The researchers hope this study will encourage providers to talk to their patients about the reasons behind their pain and discuss causes outside of biomedical ones.

“Often, discussions with patients focus on biomedical causes of pain. The role of the brain is rarely discussed,” said Ashar. “With this research, we want to provide patients as much relief as possible by exploring different treatments, including ones that address the brain drivers of chronic pain.”

Source: University of Colorado Anschutz Medical Campus

Categories : Paediatrics Pain ManagementTags :

Children’s ‘Growing Pains’ may be Tied to Migraines

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New research published in the journal Headache reveals that, in children and adolescents, pain in the lower limbs – what are often called “growing pains” by clinicians and are commonly attributed to rapid growth – may indicate the presence or risk of migraines.

The study included 100 children and adolescents born to mothers with migraines seen at a headache clinic, with half of the youth experiencing growing pains.

“In families of children with growing pains, there is an increased prevalence of other pain syndromes, especially migraine among parents,” the authors wrote. “On the other hand, children with migraine have a higher prevalence of growing pains, suggesting a common pathogenesis; therefore, we hypothesised that growing pains in children are a precursor or comorbidity with migraine.”

After five years of follow-up, 78 patients completed the study, of which 42 were from the group that experienced growing pains and 36 were from the control group. Headaches occurred in 76% of participants who had growing pains and in 22% of controls. Growing pains persisted in 14% of participants who had growing pains at the start of the study and appeared in 39% of participants who were previously asymptomatic.

“Pain in the lower limbs of children and adolescents… may reflect a precursor or comorbidity with migraine,” the authors concluded.

Source: Wiley

Categories : Pain ManagementTags :

‘Scrambler’ Therapy May Offer Lasting Relief for Chronic Pain, Review Paper Suggests

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A new review paper published in The New England Journal of Medicine suggests that scrambler therapy, a noninvasive pain treatment, can yield significant relief for 80–90% of patients with chronic pain, and it may be more effective than another noninvasive therapy: transcutaneous electrical nerve stimulation (TENS).

Scrambler therapy administers electrical stimulation through the skin via electrodes placed in areas of the body above and below where chronic pain is felt. The goal is to capture the nerve endings and replace signals from the area experiencing pain with signals coming from adjacent areas experiencing no pain, thereby ‘scrambling’ the pain signals sent to the brain, explains the study’s primary author, Thomas Smith, MD, a professor of oncology and medicine at the Johns Hopkins University School of Medicine.

All chronic pain and almost all nerve and neuropathic pain result from two things: pain impulses coming from damaged nerves that send a constant barrage up to pain centers in the brain, and the failure of inhibitory cells to block those impulses and prevent them from becoming chronic, says Smith, who also is the director of palliative medicine for Johns Hopkins Medicine.

Constantly hitting the reset button on pain

“If you can block the ascending pain impulses and enhance the inhibitory system, you can potentially reset the brain so it doesn’t feel chronic pain nearly as badly,” Smith says. “It’s like pressing Control-Alt-Delete about a billion times.”

Many patients “get really substantial relief that can often be permanent,” he says. They receive from three to 12 half-hour sessions.

As a physician who treats chronic pain, Smith says, “Scrambler therapy is the most exciting development I have seen in years – it’s effective, it’s noninvasive, it reduces opioid use substantially and it can be permanent.”

Source: John Hopkins Medicine