Many of the millions of Americans who suffer from chronic low back pain are told to just take acetaminophen. The problem? It does little to relieve their discomfort. A study published in the British Medical Journal bears this out: Researchers concluded that Tylenol and other products containing acetaminophen were no more effective than a placebo for more than 1,800 people suffering from acute lower back pain. Prescription painkillers can provide relief in the short term, but because of their serious side effects, doctors are more and more reluctant to prescribe them. But the good news is that newer, drug-free treatments are gaining traction because they are more effective.
Physical therapy and exercise are now the recommended first-line treatments and should routinely be used. A 2018 global review of guidelines from the National Institutes for Health for treatment of low back pain recommend non-pharmacological and non-invasive management, including the use of patient education and advising patients to stay active before using any medicine or surgery.
Back pain usually starts with muscle spasms — debilitating pain for short periods of time — typically triggered not by traumatic events but by mild tweaks.
“About 80% of all adults experience disabling low back pain at some point. It’s the most common cause of job-related disability and the reason behind most missed workdays,” says Rowland Hazard, MD, emeritus professor of orthopedics at the Geisel School of Medicine at Dartmouth in Hanover, New Hampshire.
More than a quarter of adults — a figure Dr. Hazard puts at 30% — reported experiencing low back pain during the past 3 months.
Once back pain episodes become more frequent and intense, doctors might refer patients to spinal and orthopedic surgeons or order magnetic resonance imaging (MRI) or another form of imaging. They might learn that their particular brand of pain is the result of spondylitis (a type of arthritis that affects the spine), spinal stenosis (narrowing of the spaces between the bones of the spine, which can create pressure on the spinal cord and nerves), arthritis or degenerative disk disease.
Acute back pain tends to resolve itself after several weeks, but for people with chronic pain, it keeps recurring — and might, in fact, never go away.
Why Back Pain Diagnoses Are Evolving
Although it’s a remarkably common health issue, back pain is tricky to treat. Even with the sophisticated imaging tools at a doctor’s disposal, such as MRIs, often there’s no clear anatomical diagnosis.
‘We’re spending billions of dollars every year on treatment, MRIs, opioids and surgeries for people with back pain,’ Dr. Hazard says. ‘At the same time, there’s a disconnect. People are not feeling better.’
“A lot of images have false positives. Things will show up that are age-related but are not what’s causing the person’s trauma,” says Dr. Hazard. “Confusion and frustration arise from the difficulty of being able to make a specific diagnosis.”
To improve treatment outcomes, doctors are beginning to shift their approaches to back pain. It’s no longer seen as a symptom, but a disease in and of itself. The spine is complex, and the pain can have a clear cause, such as a pinched nerve or herniated disk.
But it can also be a symptom of other medical conditions going on with the patient. Obesity and sedentary lifestyles, for example, also can set the stage for low back pain.
“In the last 10 years or so, a tidal wave of research demonstrates that sedentariness is substantially more impactful than previously thought,” says Stephen West, LMT, a massage therapist based in Boulder, Colorado. “And the effects of sitting for eight hours a day, on average, are not overcome merely by working out for one to two hours a day.”
Commonly Prescribed Medications for Back Pain – and Their Side Effects
Medication can be useful for short periods, but each subset has many deleterious side effects, especially for long-term use. Prescribing pain meds for back pain has become increasingly controversial and is done with greater reluctance than in previous decades.
A wide range of medications, from over-the-counter (OTC) to prescription, is used to treat low back pain. Many drugs are unsafe during pregnancy, interact with other medications poorly and lead to serious adverse effects such as liver damage or gastrointestinal ulcers and bleeding. The following are five main types of medicine-based low back pain treatments:
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
This class of drugs relieves pain and inflammation and includes OTC formulations such as ibuprofen, ketoprofen, and naproxen sodium as well as the COX-2 inhibitor celecoxib, available only by prescription. Long-term use of NSAIDs is not recommended because of the risk of stomach irritation, ulcers, heartburn, diarrhea, fluid retention and in rare cases, kidney dysfunction and cardiovascular disease.
One study that reviewed the evidence from 65 NSAIDs trials found that NSAIDs were effective for short-term symptomatic relief in patients with acute and chronic low back pain without sciatica (pressure on the sciatic nerves down the legs, which causes pain). However, the effect sizes were small. A follow-up review of studies focused on NSAIDs for low back pain found similar results. And a review of 35 studies by researchers at the University of Sydney in Australia found that only about one in six people that take NSAIDs actually feel any benefit from it. The researchers reviewed studies that examined the effect of NSAIDs in easing back pain. In addition, those on NSAIDs were 2 ½ times more likely to experience gastrointestinal side effects compared with those on placebo.
Research shows that the prescription COX-2 inhibitor, celecoxib, appears to be no more effective than ibuprofen or naproxen but it comes with fewer side effects. A 10-year study conducted by Pfizer, the maker of the celecoxib brand Celebrex, involving more than 24,000 people were given either Celebrex, ibuprofen or naproxen. People taking ibuprofen had a 64% higher risk of kidney failure compared to those on celecoxib. Those on celecoxib also had fewer ulcers and gastrointestinal bleeding compared to those on NSAIDs.
Interactions of NSAIDs
And in light of potential drug interactions, many drugs can’t be taken in conjunction with NSAIDs. For example, patients with an irregular heartbeat who take a blood thinner as well as an NSAID are much more likely to experience major bleeding and stroke compared to those not on a pain killer.
Researchers looked at results from a trial that included more than 18,000 patients and compared Pradaxa (dabigatran) to warfarin, both blood thinners, in patients with atrial fibrillation, an irregular and sometimes rapid heartbeat that can increase one’s risk for heart failure or stroke. Of that number, 12.5% used an NSAID – such as ibuprofen or naproxen during the trial.
Results, published in the Journal of the American College of Cardiology, indicated that bleeding rates were substantially higher, no matter which anticoagulant was used, in those that also took an NSAID. Also, patients taking both a blood thinner and an NSAID were more likely to experience a stroke and need hospitalization. However, rates of death were similar whether or not a patient was taking an NSAID.
Combining blood pressure drugs — specifically angiotensin-converting enzyme (ACE) inhibitors, angiotensin-receptor blockers (ARBs), and diuretics — with NSAIDs can also lead to problems. These meds work on the kidneys, which are the source of hypertension in some cases.“NSAIDs slow down kidney function, which can, in turn, interfere with the blood pressure medication’s actions,” explains Heather Free, PharmD, AAHIVP, a spokesperson for the American Pharmacists Association. “NSAIDs can also increase fluid retention, which can make it even more difficult to pump blood back to the heart, straining the kidneys and heart and putting the patient at more risk for complications.”
Further evidence of drug interaction risks appears in a study published in Gastroenterology. The already-high risk of gastrointestinal (GI) bleeding associated with NSAIDs increased significantly when taken in combination with corticosteroids, diuretics, or anticoagulants in a study of 113,835 patients with an upper GI bleed. Researchers determined that non-selective NSAIDs, such as ibuprofen, increased upper GI bleeding more than COX-2 inhibitors or low-dose aspirin.
Specifically designed to relieve pain, analgesic medications include OTC acetaminophen and aspirin. Outcomes are controversial — relief tends to be small to negligible — given the risk of hypertension and other side effects. In fact, the number one cause of acute liver failure is too much acetaminophen. Either a single high overdose or dosing at the max for multiple days could lead to liver damage or failure.
In an effort to reduce the risk of taking too much acetaminophen — which is also combined with other ingredients in hundreds of OTC cough, cold, flu, and other products — the FDA has taken action to educate the public and improve consumer safety when using the drug. For example, the FDA’s Safe Use Initiative is intended to help prevent liver damage and death in infants when parents accidentally give them a concentrated formula of acetaminophen designed for older kids. Or when a parent gives the second dose too soon because of misreading the instructions, or simple parent fatigue.
Both acetaminophen and ibuprofen have been implicated in hearing loss in some older women when used over the long term. Researchers at Boston’s Brigham and Women’s Hospital examined data from more than 54,000 women, aged 48 to 73 years old, that took part in the Nurses’ Health Study. They analyzed information on the use of acetaminophen, ibuprofen and aspirin, as well as self-reported hearing loss.
The longer the women used ibuprofen or acetaminophen, the higher the risk of hearing loss, the researchers reported in the American Journal of Epidemiology. There was no significant association between hearing loss and duration and the usual dose of aspirin.
“Although the magnitude of higher risk of hearing loss with analgesic use was modest, given how commonly these medications are used, even a small increase in risk could have important health implications,” senior author Gary Curhan, MD, said in a statement. “Assuming causality, this would mean that approximately 5.5% of hearing loss occurring in these women could be due to ibuprofen or acetaminophen use.”
On another note, acetaminophen appears to make people less likely to empathize with others in pain. That’s the conclusion of a study published in the journal Social Cognitive and Affective Neuroscience, conducted a The Ohio State University. In two experiments, they found that when subjects who took acetaminophen learned about the misfortunes of others, they thought these individuals experienced less pain and suffering when compared to those who took no painkiller.
The researchers said they are not sure exactly why acetaminophen appears to blunt empathy towards others. “These findings suggest other people’s pain doesn’t seem as big of a deal to you when you’ve taken acetaminophen,” said Dominik Mischkowski, PhD, a study co-author and an assistant professor of psychology at Ohio University College of Arts and Sciences. “Acetaminophen can reduce empathy as well as serve as a painkiller.”
Analgesics also include prescription opioids such as codeine, oxycodone, hydrocodone, and morphine.
“Opioids as a group expose people to the risks of tolerance and addiction,” says Santhosh Thomas, DO, who specializes in orthopedic surgery of the spine at the Cleveland Clinic in Ohio. “They should be used in conjunction with some other intervention. Opioids shut off signals to the brain and can dull pain, but they don’t fix the problem.”
Whether or not opioids are worth the risks is a question worth considering. In a 2018 study, researchers found that taking opioids didn’t provide much more relief than a placebo, but came with many side effects. After reviewing about 100 studies involving opioids for chronic pain, researchers said that the modest benefits of opioids tend to wane over time, but come with unpleasant side effects such as constipation and vomiting. Even more concerning, they say, is the increased risk for physical dependence with long-term use. (See MedShadow’s 3 Steps From Pain Management To Heroin) The meta-analysis found that compared to a placebo, 12% more patients taking opioids had pain relief, 8% more had physical functioning improvements and 6% more had better sleep.
Dr. Thomas recommends long-acting opioids (LAO) rather than short-acting opioids (SAO) because LAOs release the drug more gradually into the bloodstream so as not to cause a rapid increase and decrease in serum levels.
In the past it’s been difficult for doctors to prescribe opioids, Dr. Hazard says, as there were no fixed guidelines for dosage. But in 2016 the Centers for Disease Control and Prevention (CDC) developed the CDC Guideline for Prescribing Opioids for Chronic Pain that includes a checklist for healthcare providers to review when considering prescribing opioids.
In 2017 the National Academies of Science, Engineering, and Medicine issued a report to the Food and Drug Administration (FDA) calling for a new action plan to fight the opioid abuse epidemic. The report calls for a new action plan that would require the FDA, other federal agencies, state and local governments, healthcare providers, and other health organizations to work together in a long-term effort.
Recommendations included promoting more judicious prescribing of opioids, boosting access to treatment for opioid abuse, preventing more overdose deaths, and spending more money on research to understand pain better and develop alternatives that are not addictive.
The report recommended that education about the risks and benefits of opioids should be improved for both the general public and healthcare providers. Pain-related education should be mandatory for doctors that treat people with pain, while basic training in the treatment of opioid use disorders should be provided for other healthcare professionals. Prescribers and pharmacists should also be trained to recognize patients who are at risk for abuse or overdose and how to help them.
In 2018, following the Academies’ recommendations, the FDA approved an Opioid Analgesic Risk Evaluation and Mitigation Strategy for providers to reduce the risk of abuse, misuse, addiction, overdose, and deaths due to prescription opioid analgesics.
Aside from the obvious risks for increased drug tolerance, abuse and addiction, Dr. Hazard says that other common side effects of opioids are headaches, sedation, constipation, hypogonadism, decreased reaction time and impaired judgment. For long-term opioid use, says Hazard, you need to have a steady relationship with your provider. Over half of Americans are misusing their prescription drugs, including powerful opioid painkillers, according to a study examining patient lab tests. Quest Diagnostics examined more than 3.4 million lab tests taken between 2011 and 2016 involving prescription medications and found that 52% of these specimens indicated misuse, such as not taking a drug according to their doctor’s orders. Essentially, “every other American tested (positive) for inappropriate use of opioids and other prescription drugs,” F. Leland McClure, PhD, a director at Quest, said in a statement.
More than 33,000 specimens were tested by Quest for opioid, benzodiazepine (a type of tranquilizer medication) and alcohol use last year. Results showed that more than 20% of those tested were positive for both opioids and benzodiazepines, 10% were positive for taking opioids and alcohol, and 3% were positive for taking all 3. Because both opioids and benzodiazepines can slow down the body’s central nervous system, when taken together trouble breathing, heart problems and even a risk of a fatal overdose are possible.
In a 2019 update that looked at 4.4 million lab tests through 2018, Quest found that trends in misuse of prescription drugs may have plateaued, but there is still a long way to go. Signs of misuse appeared in 51% of test results, with 24% testing positive for drug mixing.
Nearly all states now have prescription drug monitoring programs to track prescriptions for opioids and other controlled substances, and these programs have been successful in reducing opioid use. In a 2019 study, researchers at Weill Cornell Medicine in New York City looked at opioid prescription data reported by state programs from 2011 to 2016. They found that states with mandates for prescription drug monitoring programs saw an 8.92 percent reduction in the number of opioid prescriptions, as well as 4.27 percent fewer hospital stays and 17.75 percent fewer emergency department visits related to opioid use. The researchers estimate that this could amount to a reduction of about 12,000 inpatient hospital stays and 39,000 emergency department visits. States that didn’t require prescribers and distributors of opioids to register with and use the programs saw no reductions in opioid use in these areas.
More on opioids from MedShadow
Drugs primarily used to treat seizures may be useful in treating people with radiculopathy and radicular pain, a pain caused by nerve damage. They work by causing changes in the electric signals in the brain. Anticonvulsants most often used to treat chronic pain are carbamazepine (Tegretol) gabapentin (Neurontin). Common side effects include dizziness, drowsiness, weight gain or weight loss, upset stomach, loss of appetite, skin rashes, or feeling confused, depression, and headaches.
Tricyclics, serotonin and norepinephrine reuptake inhibitors are commonly prescribed for chronic low back pain to provide pain relief, help with sleep and reduce depression. Antidepressants may increase neurotransmitters in the spinal cord that reduce pain signals. In a 2018 study of the tricyclic antidepressant amitriptyline, taken at a low dose for chronic low back pain, patients experienced an improvement in disability after three months and a nonsignificant improvement in pain intensity at six months. The researchers concluded that amitriptyline may be an effective treatment for chronic low back pain, particularly if the only alternative is an opioid.
Like anticonvulsants, one of the biggest risks is sedation. Other common side effects include dry mouth, constipation, blurred vision, weight gain, problems urinating, and sexual problems. Less commonly, some of these drugs can also cause heart and lung problems. Sleep and stomach issues are not uncommon two to four weeks into treatment. (See MedShadow’s Coping With the Side Effects of Antidepressants)
Epidural steroid injections
Steroid injections are a commonly used short-term option for treating low back pain associated with inflammation. Pain relief tends to be temporary and there is a low risk of spinal infection and nerve damage as well as the more frequent severe headache. In a 2012 study, patients given steroid treatments didn’t experience much pain relief in either the short or long term, nor did researchers find a significant difference in pain relief when they compared patients who had received steroid injections with those who didn’t. In a 2013 study published by Anesthesiology, epidural shots for back pain seem to be equally effective with saline only (inactive placebo) versus steroid solutions.
And in a study published in 2017 in the Annals of Internal Medicine, getting steroid injections to alleviate lower back pain only offered short-term relief. Researchers in France examined 145 patients that complained of lower back pain. On average, they suffered from back pain for six years. Some of the participants received a steroid injection, while others received no treatment. Patients were asked to rate the severity of their pain at the study start, and again one, three, six and 12 months later.
A month after treatment, 55% of those who got the injection experienced less lower back pain, compared with 33% who didn’t receive an injection. However, 12 months after the study began, there was no difference in pain outcomes between those who got the injection and those who didn’t. In addition, at 12 months, the two groups had similar rates of disc inflammation, lower quality of life, more anxiety and depression, and the use of pain medication.
Your Best Drug-Free Treatment Options for Back Pain
As the tide turns against medication as a viable solution for back pain, alternative treatments such as physical therapy, core strengthening, exercise, and massage have emerged as effective strategies. (See MedShadow’s For Back Pain, Try Non-Drug Measures First)
“Medications don’t have a whopping track record,” says Dr. Hazard. “Intensive rehabilitation does. It’s a multidisciplinary approach called Functional Rehabilitation that includes occupational therapy, physical therapy (PT), physical training, counseling and instruction in pain management.”
Dr. Thomas cites PT as the earliest intervention he recommends his patients to try, along with lifestyle changes such as weight loss and kicking smoking.
A 2011 study published in Annals of Internal Medicine Massage showed that participants in massage groups reported greater average improvements in pain and functioning compared to those in the usual care group that included a range of options: taking pain medications or muscle relaxants, seeing doctors or chiropractors, physical therapy, or simply not doing anything. No clinically meaningful difference between relaxation (Swedish) and the structural massage was observed in terms of relieving disability or symptoms, however.
Soft tissue work can be surprisingly effective at relieving pain, says West. He recommends finding a practitioner experienced with pathology and musculoskeletal issues. (See MedShadow’s Is Therapeutic Massage Right for Me?)
A study published in February 2009 recommends that in most cases of symptomatic lumbar degenerative disk disease, a common cause of low back pain, the most effective treatment is physical therapy combined with anti-inflammatory medications. Exercise and manual therapy including spinal manipulation as well as educating patients in the use of appropriate body mechanics has a good track record of benefit.
In a 2018 global review of guidelines for the treatment of low back pain, researchers conclude that the physical therapy and exercise approach is a first-line treatment and should routinely be used. They recommend non-pharmacological and non-invasive management, including the use of patient education and advising patients to stay active.
Victor Hoover, a 47-year-old engineer based in Corpus Christi, Texas, who has suffered from back pain almost daily for roughly two decades, says he’s tried everything to help relieve it. What works best, he says, is a foam roller. Foam rollers, popular among physical therapists, untie the knots in your muscles by breaking down adhesions and helping to heal the tissue.
“It’s like aggressive physical therapy,” says Hoover. “For me, it’s worked better than stretching or light exercise, and I do it several times a week before I go to bed. Nothing else has lasted as long, in terms of benefit.”
Some physical therapists might try transcutaneous electrical nerve stimulation (TENS) for short-term pain. The treatment, which stimulates nerves around the spine in an attempt to change the messages sent to your brain’s pain receptors, isn’t painful but hasn’t been shown to be an effective treatment for chronic low back pain.
Exercise and Yoga
“Prevention is by far the best way to prevent back pain,” says West. And not sitting is high on the list. You shouldn’t sit more than 20 minutes at a time without a movement break and strategize ways for not sitting for long periods of time, even when taking into account the time you spend driving.
If it’s too late for prevention, low-impact exercise can help reduce your pain. Walking and swimming are two non-jarring activities doctors and physical therapists recommend. Also note that toned abdominal muscles are essential for back health (they help create a natural “girdle” that helps support your spine): Pilates, yoga or specific, targeted exercises (such as “swimming” moves that strengthen the back muscles) that support your spine are good ways to keep your core strong and reinforce your alignment awareness. Eric Volk, 43, a stay-at-home dad and part time marketer who lives in Lyons, Colorado, describes yoga as “poor man’s massage, because you have to do the work yourself without the help of a massage therapist.”
Studies show that yoga may have some benefit for people with low back pain. An analysis of 12 studies encompassing more than 1,000 participants with lower back pain compared yoga to physical therapy or patient education.
Compared to no exercise, yoga may improve back-related function and may also reduce symptoms of lower back pain by a small amount in the first six to 12 months, according to an analysis published in the Cochrane Review.
The results also showed that yoga may cause an increase in back pain in some people. About 5% of yoga participants experienced increased back pain, although this may be similar to the risk of side effects from other back-focused exercise poses.
“Our findings suggest that yoga exercise may lead to reducing the symptoms of lower back pain by a small amount,” said review author Susan Wieland, MD, a professor at the University of Maryland School of Medicine. “At the moment we only have low to moderate quality evidence for the effects of yoga before six months as a type of exercise for helping people with chronic lower back pain.”
Ideally, proper alignment of your body, the best defense against backaches, is integrated into all of one’s movements, including everyday activities such as walking, lifting, bending and gardening.
Relaxation and Meditation
There’s some evidence that mind-related techniques, including hypnosis, meditation and biofeedback can be effective additions to a chronic pain management program; ask your doctor or physical therapist for advice or referrals.
In fact, research shows that non-drug treatments such as mindfulness and cognitive-behavioral therapy (CBT) can be more effective than medication and without the side effects.
Researchers examined 21 clinical trials that enrolled 2,000 people. They focused on CBT and mindfulness-based stress reduction as therapies for chronic pain in those trials. The latter involves meditation and simple yoga poses.
Patients in the studies had pain resulting from arthritis, fibromyalgia and temporomandibular joint disorder (TMJ), which involves the jaw. Some dealt with lower back pain.
Results, published in the journal Evidence-Based Mental Health, found that changes in physical functioning, pain intensity and depression were better in those who engaged in CBT and mindfulness compared to those who took medication. However, the researchers noted that those effects were “small.”
Many doctors discourage patients from surgical treatment for chronic back pain. Surgical treatments should be considered a last resort, says Dr. Thomas, and only considered after all other treatments have failed to provide relief. Even then, surgery does not provide significant improvement for everyone and is associated with serious risks.
Two general types of surgery comprise the most common procedures for the lower back: decompression (including laminectomy and diskectomy) and fusion.
- Spinal laminectomy Laminectomy (sometimes called decompression) is performed when spinal stenosis causes a narrowing of the spinal canal that causes pain, numbness or weakness. The surgeon removes part or all of the vertebral bone (lamina) to relieve compression of the spinal cord and remove pressure on the nerves. Reported outcomes vary, but a 2016 study in Frontiers in Surgery reports that about 64% of such surgeries are successful.
- Diskectomy In a diskectomy, surgeons remove the damaged portion of a herniated disk in your spine. Laminectomy and diskectomy are frequently performed together and the combination is one of the more common ways to remove pressure on a nerve root from a herniated disk or bone spur.
Volk first experienced back pain at age 17. He is now 43 and has had two laminectomy/diskectomy operations. His first, when he was 29, was considered a success. However, the disk weakened and was compromised — he had a recurrent disk herniation several years later. After a second surgery six years later, his back was still in bad shape. His doctor recommends spinal fusion, but Volk fears that the more invasive surgery can ultimately lead to disk deterioration.
- Spinal fusion Spinal fusion is used to strengthen the spine and prevent painful movements in people with degenerative disk disease or spondylolisthesis (following laminectomy). Spondylolisthesis is a slipping of vertebra that occurs most often at the base of the spine. The spinal disk between two or more vertebrae is removed and the adjacent vertebrae are “fused” by bone grafts and/or metal devices secured by screws. Success is dependent on many factors, but the rate of improvement after the surgery can be as high as 60% to 90%, according to the University of Rochester Medical Center. Being a smoker, for example, can diminish chances that back surgery is successful.
Cigarette smoking causes a number of problems for patients undergoing spinal fusion, including a significantly decreased rate of successful fusion (called nonunion or pseudarthrosis).“We won’t operate on smokers with spine-related issues because of the higher failure rate,” says Dr. Thomas.
Note that spinal fusion might result in some loss of flexibility in the spine and requires a long recovery period to allow the bone grafts to grow and fuse the vertebrae together. The procedure also has been associated with an acceleration of disk degeneration at adjacent levels of the spine. Also worth noting: a report in the journal Spine in 2019 noted that the number of spinal fusion surgeries performed rose 62% between 2004 and 2015. The report concludes that the rate increased the most for scoliosis and spondylolisthesis, both are considered relatively effective. The rate for fusions with other, generally less effective, have decreased slightly.
For More Information
- American Physical Therapy Association
- National Institute of Neurological Disorders and Stroke
- University of Rochester Medical Center Integrated Spine Center
- Treatment Options for Low Back Pain (American Academy of Orthopaedic Surgeons video)
- American Association of Neurological Surgeons
- Chronic Pain Management Techniques (Spine-Health.com)
- A Comparison of Long- and Short-Acting Opioids for the Treatment of Chronic Noncancer Pain: Tailoring Therapy to Meet Patient Needs (PubMed Central)
- Spinal Cord Stimulator (Johns Hopkins Medicine)