1. Is there a genetic risk for substance abuse and is there a statistical risk calculator for substance abuse based on a patient’s family history? There is no simple method of assessing substance abuse risk based on genetics or family history. Studies of twins have found drug addiction to be 40% to 70% hereditary, as well as dependent on the drug being evaluated. First-degree relatives are at higher risk than other relatives, but it is not clear how to assess the level of risk in other relatives in a long-term, reliable manner. In addition, there is no Mendelian model of inheritance for addiction, and the genetic relationships can be very complex. The risk of substance abuse also depends on environmental (e.g., exposure) and other factors. When a patient is initiated on opioids, a history of prior substance abuse may be the strongest risk factor for future abuse, although family history is also an important risk factor, but to a lesser extent. There is currently a tool available to broadly assess the risk of opioid misuse and abuse – the OpioidRisk Tool – and both family and personal factors will be involved in risk stratification for substance abuse. 2.What kinds of patients and treatments lead to opioid-related mental disorders? The greatest risk factor for opioid-induced psychiatric disorders is a history of opioid use or other substance abuse. A familial history of substance abuse is another important risk factor. Some studies suggest that depression and other psychiatric comorbidities, age 20-40 years, and females who were sexually abused before puberty are risk factors. Other studies have identified somatization symptoms as a risk factor. In terms of treatment, the use of short- or long-acting opioids, specific opioids, or dosage (although dosage may lead to dose-dependent accidental overdose), the correlation between these factors and substance abuse is unclear. 3. In what ways do opioids affect cognition and driving ability? Opioids can cause cognitive delays and decreases in reflexes and attention, especially when they are first taken and when the dose is changed. However, some studies have found, through simulated driving tests, that taking stable doses of opioids does not impair driving ability. Other studies have also concluded that long-term use of stabilized doses of opioids does not increase the incidence of motor vehicle accidents. However, patients should be informed of the potential risk of opioids affecting cognition, driving, and job safety, and should avoid driving when impairment occurs, as well as avoiding other substances and medications that can affect cognition and driving, and avoiding driving when first starting to take opioids or when changing doses. 4. Is it possible to manage chronic pain by taking short- or long-acting opioids for long periods of time? Although long-acting, continuous-use opioids are recommended for the treatment of chronic pain, there is no evidence to suggest that they are superior to short-acting medications or on-demand dosing. The advantages of long-acting, sustained-use opioids include fewer peaks and valleys in blood levels (which theoretically reduces drug addiction or withdrawal syndromes) and longer-lasting pain control. However, long-acting, continuous use of opioids is likely to lead to tolerance and a gradual increase in drug dosage. No studies have shown that long-acting opioids provide more effective pain relief than short-acting opioids. The bottom line is that both can be used, and there is no need to switch patients to long-acting opioids if they are doing well on short-acting opioids and vice versa. Despite the persistent claims of benefit from long-acting opioids, no studies to date have concluded that chronic pain patients receiving long-acting opioids achieve pain relief superior to short-acting opioids. In fact, at least one “head-to-head” study has concluded the opposite. Each patient’s chronic pain can be addressed with a different opioid regimen. All we need to do is determine which treatment option is more appropriate for that patient. 5. Is there evidence that long-acting opioids are effective for chronic pain? The current evidence supporting that long-acting opioids are effective in treating chronic pain is quite limited. There has not been a single randomized study of opioids versus blank controls for longer than 6 months, and most patients were treated for less than 6 weeks. A Cochrane review of studies with little data from uncontrolled studies (e.g., clinical studies in which patients were randomly assigned to an opioid group and then followed until the end of the study) showed that some of the patients were on opioids for a long period of time and received sustained pain relief, although a large proportion discontinued treatment due to side effects or ineffectiveness of the medication. Therefore, more long-term controlled studies are needed in the future to conduct comparative analyses of long-acting opioids versus other therapies (blank controls, no opioids or non-opioid substitution). Population-based controlled studies are represented by their design, ignoring individual responses. This type of controlled study is often ignored at this point if one wants to know whether patients responded well to opioids for 1, 2, or many years, as well as the duration of poor efficacy. Therefore, there is a need to design a more clinically integrated approach to study this issue. 6 What is the evidence supporting multimodal treatment of pain? For chronic pain with functional impairment, multidisciplinary collaborative rehabilitation-a multimodal treatment program that includes integration between physical therapy, psychotherapy (e.g., cognitive-behavioral therapy), and other therapies-has been shown to be more effective than a single-modality treatment program. For lower back pain, when patients do not have radiating pain to the lower extremities, multidisciplinary rehabilitation is comparable to interbody fusion. For the majority of patients, there is not much evidence that the cumulative effect of multiple interventions is superior to a single one or a few, especially when patients have concomitant acute pain. When patients present with chronic dysfunctional pain and a single intervention is ineffective, or when there is a possibility of progression to chronic dysfunctional pain, a multimodal treatment program can be more beneficial. Unfortunately, the multimodal pain treatment options recommended above have rarely been reported in prospective studies with large sample sizes. Many studies have found that it is difficult for a single intervention to provide complete or significant relief of chronic pain in most patients. 7, There are internists who treat pain usually by adding a second opioid, rather than increasing the dose of the initial medication. Any suggestions for changing this practice that leads to both confusion in care and failure to improve patient experience? This can easily be flagged through the electronic prescription record, which in turn gets the attention of physicians so they maintain one opioid instead of more. Some patients are perfectly capable of benefiting from a single opioid, and experience has shown that the best practice is to have one opioid as a long-acting medication (e.g., fentanyl patch) and another opioid for the treatment of eruptive pain (e.g., short-acting OxyContin or oxymorphone). Recently there has been a growing clinical interest in a new dosage form that combines morphine and Oxycontin, and some studies have suggested that this combination may increase efficacy. This formulation has not yet been approved by the FDA. 8. Can I use buprenorphine while breastfeeding? Taking medication while breastfeeding is a very important topic of discussion between the mother and her doctor. It is possible to continue to use buprenorphine during breastfeeding because the level of buprenorphine in breast milk and therefore in the newborn is very low. Many newborns may experience withdrawal syndrome when their mothers take methadone or buprenorphine, and the small amount of buprenorphine in breast milk may attenuate this response. 9. What can I do to avoid opioid-induced nociceptive sensitization? There is very limited understanding of the prevalence and clinical impact of nociceptive sensitization and how to avoid it. In clinical practice, it is difficult to distinguish between nociceptive sensitization and drug tolerance. Some evidence suggests that nociceptive sensitization occurs with relatively high doses of opioids, and is relatively uncommon when below the 120 mg morphine equivalent dose per day. Some studies have suggested that blocking NMDA receptors (e.g., dextromethorphan, ketamine, or methadone) might inhibit nociceptive sensitization, but a great deal of research is needed before recommending the use of these medications based on that purpose, as each of these medications carries its own potential risks. There are no high-quality studies to support or refute these ideas. 10. How can non-physicians (e.g., psychotherapists, physical therapists, pharmacists, nurses) who provide pain management to patients collaborate with physicians? Non-physicians should also educate patients about the importance of self-care and exercise while avoiding reinforcing negative behaviors such as fear avoidance and catastrophizing. Similarly, neither internists nor occupational physical therapists should overemphasize imaging findings (e.g., degenerative changes in the low back), which are common and weakly related to pain, but should emphasize the importance of exercise and that exercise does not further injure the low back. Consistent treatment advice can urge patients to begin exercising, with subsequent improvement in function. When non-physicians have concerns about opioid regimens (e.g., the patient is offered another physician’s regimen) or the patient’s outcomes are poor, they should communicate with the physician, which can help the physician develop a treatment plan for the future. Communication and mutual respect for each other’s treatment principles and protocols are critical. This last point in particular is often overlooked in current principles of drug therapy, given that no single treatment regimen works for everyone or cures the patient, and the importance of individualized treatment. Good communication with each other will allow the patient to benefit more from his or her treatment, and it is not possible to “unthinkingly agree” that a treatment will be effective. Finally, it is important to realize how each intervention helps the patient. For example, what is the role of opioids in the multimodal management of chronic pain? What role do physical and occupational therapy, invasive pain management, or cognitive-behavioral therapy all play? As most people know, it is usually not one treatment alone that cures a patient, and there is great value in integrating these different perspectives in a patient’s treatment strategy. 11. How do you deal with those addicted patients who seek treatment? This group of patients is recognized as a difficult group to deal with. It should be recognized that opioids are only one type of chronic pain medication. When a patient exhibits these behaviors, other appropriate non-opioid medications and certainly non-pharmacological means of treatment can be considered. This group of patients should be handled humanely and safely.